Cycloalkyl alkanoic acids as integrin receptor antagonists

ABSTRACT

The present invention relates to a class of compounds represented by the Formula I  
                 
 
     or a pharmaceutically acceptable salt thereof, pharmaceutical compositions comprising compounds of the Formula I, and methods of selectively inhibiting or antagonizing the α V β 3  and/or α V β 5  integrin.

[0001] The present application claims priority under Title 35, UnitedStates Code, §119 of U.S. Provisional application Serial No. 60/211,781filed Jun. 15, 2000.

FIELD OF THE INVENTION

[0002] The present invention relates to pharmaceutical agents(compounds) which are α_(V)β₃ and/or α_(V)β₅ integrin antagonists and assuch are useful in pharmaceutical compositions and in methods fortreating conditions mediated by α_(V)β₃ and/or α_(V)β₅ integrins.

BACKGROUND OF THE INVENTION

[0003] The integrin α_(V)β₃ (also known as vitronectin receptor), is amember of the integrin family of heterodimeric transmembraneglycoprotein complexes that mediate cellular adhesion events and signaltransduction processes. Integrin α_(V)β₃ is expressed in number of celltypes and has been shown to mediate several biologically relevantprocesses, including adhesion of osteoclasts to the bone matrix,vascular smooth muscle cell migration and angiogenesis.

[0004] The integrin α_(V)β₃ has been shown to play a role in variousconditions or disease states including tumor metastasis, solid tumorgrowth (neoplasia), osteoporosis, Paget's disease, humoral hypercalcemiaof malignancy, osteopenia, angiogenesis, including tumor angiogenesisand lymphangiogenesis, retinopathy including macular degeneration,arthritis, including rheumatoid arthritis, periodontal disease,psoriasis and smooth muscle cell migration (e.g. restenosisartherosclerosis). The compounds of the present invention are α_(V)β₃antagonists and can be used, alone or in combination with othertherapeutic agents, in the treatment or modulation of various conditionsor disease states described above. Additionally, it has been found thatsuch agents would be useful as antivirals, antifungals andantimicrobials.

[0005] The integrin α_(V)β₅ is thought to play a role inneovascularization. M. C. Friedlander, et al., Science, 270, 1500-1502(1995) disclose that a monoclonal antibody for α_(V)β₅ inhibitsVEFG-induced angiogenesis in the rabbit cornea and the chickchorioallantoic membrane model. Therefore compounds which act asantagonists of the α_(V)β₅ integrin will inhibit neovascularization andwill be useful for treating and preventing angiogenesis metastasis,tumor growth, macular degeneration and diabetic retionopathy.

[0006] Certain compounds may antagonize both the α_(V)β₅ and the α_(V)β₃receptor and therefore are referred to as “mixed α_(V)β₅/α_(V)β₃antagonists” or “dual α_(V)β₃/α_(V)β₅ antagonists”. Such dual or mixedantagonists are useful for treating or preventing angiogenesis, tumormetastasis, tumor growth, diabetic retinopathy, macular degeneration,atherosclerosis and osteoporosis.

[0007] It has been shown that the α_(V)β₃ integrin and other α_(V)containing integrins bind to a number of Arg-Gly-Asp (RGD) containingmatrix macromolecules. Compounds containing the RGD sequence mimicextracellular matrix ligands so as to bind to cell surface receptors.However, it is also known that RGD peptides in general are non-selectivefor RGD dependent integrins. For example, most RGD peptides which bindto α_(V)β₃ also bind to α_(V)β₅, α_(V)β₁ and α_(IIb)β₃. Antagonism ofplatelet α_(IIb)β₃ (also known as the fibrinogen receptor) is known toblock platelet aggregation in humans. In order to avoid bleedingside-effects when treating the conditions or disease states associatedwith the integrin α_(V)β₃, it would be beneficial to develop compoundswhich are selective antagonists of α_(V)β₃ as opposed to α_(IIb)β₃.Tumor cell invasion occurs by a three step process: 1) tumor cellattachment to extracellular matrix; 2) proteolytic dissolution of thematrix; and 3) movement of the cells through the dissolved barrier. Thisprocess can occur repeatedly and can result in metastases at sitesdistant from the original tumor.

[0008] Seftor et al. (Proc. Natl. Acad. Sci. USA, Vol. 89 (1992)1557-1561) have shown that the α_(V)β₃ integrin has a biologicalfunction in melanoma cell invasion. Montgomery et al., (Proc. Natl.Acad. Sci. USA, Vol. 91 (1994) 8856-60) have demonstrated that theintegrin α_(V)β₃ expressed on human melanoma cells promotes a survivalsignal, protecting the cells from apoptosis. Mediation of the tumor cellmetastatic pathway by interference with the α_(V)β₃ integrin celladhesion receptor to impede tumor metastasis would be beneficial.

[0009] Further, with the discovery that α_(V)β₃ plays a role in theprocess of lymphatic dissemination via adhesion of melanoma cells tolymph node by binding the vitronectin receptor (Nip et al, J Clin Invest1992, 90,1406), inhibitors of α_(V)β₃ may also be useful for makingalterations in lymphatic endothelial-tumorcell adhesion, thereby furtherreducing the potential for tumor metastasis.

[0010] Brooks et al. (Cell, Vol. 79 (1994) 1157-1164) have demonstratedthat antagonists of α_(V)β₃ provide a therapeutic approach for thetreatment of neoplasia (inhibition of solid tumor growth) since systemicadministration of α_(V)β₃ antagonists causes dramatic regression ofvarious histologically distinct human tumors.

[0011] The compounds of the present invention are useful for thetreatment, including prevention of angiogenic disorders. The termangiogenic disorders include conditions involving abnormalneovascularization. The growth of new blood vessels, or angiogenesis,also contributes to pathological conditions such as diabetic retinopathyincluding macular degeneration (Adam is et al., Amer. J. Ophthal., Vol.118, (1994) 445-450) and rheumatoid arthritis (Peacock et al., J. Exp.Med., Vol. 175, (1992), 1135-1138). Therefore, α_(V)β₃ antagonists wouldbe useful therapeutic agents for treating such conditions associatedwith neovascularization (Brooks et al., Science, Vol. 264, (1994),569-571).

[0012] It has been reported that the cell surface receptor α_(V)β₃ isthe major integrin on osteoclasts responsible for attachment to bone(for a review, see Rodan and Rodan, 1997, J. Endocrinol. 154, S47,Nakamura et al., J. Cell Science, 1999 112, 3985). Osteoclasts causebone resorption and when such bone resorbing activity exceeds boneforming activity it leads to an increased number of bone fractures,incapacitation and increased mortality. Antagonists of α_(V)β₃ have beenshown to be potent inhibitors of osteoclastic activity both in vitro(Sato et al., J. Cell. Biol., Vol. 111 (1990) 1713-1723) and in vivo(Fisher et al., Endocrinology, Vol. 132 (1993) 1411-1413). Antagonism ofα_(V)β₃ leads to decreased bone resorption and therefore restores anormal balance of bone forming and resorbing activity. Thus it would bebeneficial to provide antagonists of osteoclast α_(V)β₃ which areeffective inhibitors of bone resorption and therefore are useful in thetreatment or prevention of osteoporosis.

[0013] The role of the α_(V)β₃ integrin in smooth muscle cell migrationalso makes it a therapeutic target for prevention or inhibition ofneointimal hyperplasia which is a leading cause of restenosis aftervascular procedures (Choi et al., J. Vasc. Surg. Vol. 19(1) (1994)125-34). Prevention or inhibition of neointimal hyperplasia bypharmaceutical agents to prevent or inhibit restenosis would bebeneficial.

[0014] White (Current Biology, Vol. 3(9)(1993) 596-599) has reportedthat adenovirus uses α_(V)β₃ for entering host cells. The integrinappears to be required for endocytosis of the virus particle and may berequired for penetration of the viral genome into the host cellcytoplasm. Thus compounds which inhibit α_(V)β₃ would find usefulness asantiviral agents.

SUMMARY OF THE INVENTION

[0015] The compounds of this invention are 1) α_(V)β₃ integrinantagonists; or 2) α_(V)β₅ integrin antagonists; or 3) mixed or dualα_(V)β₃/α_(V)β₅ antagonists. The present invention includes compoundswhich inhibit the respective integrins and also includes pharmaceuticalcompositions comprising such compounds. The present invention furtherprovides for methods for treating or preventing conditions mediated bythe α_(V)β₃ and/or α_(V)β₅ receptors in a mammal in need of suchtreatment comprising administering a therapeutically effective amount ofthe compounds of the present invention and pharmaceutical compositionsof the present invention. Administration of such compounds andcompositions of the present invention inhibits angiogenesis, tumormetastasis, tumor growth, osteoporosis, Paget's disease, humoralhypercalcemia of malignancy, retinopathy, macular degeneration,arthritis, periodontal disease, smooth muscle cell migration, includingrestenosis and artherosclerosis, and viral diseases.

[0016] Further, it has been found that the selective antagonism of theα_(V)β₃ integrin is desirable in that the α_(V)β₆ integrin may play arole in normal physiological processes of tissue repair and cellularturnover that routinely occur in the skin and pulmonary tissue, andα_(V)β₈ may play a role in the regulation of growth in the humanpathway. Therefore, compounds which selectively inihibit the α_(V)β₃integrin as opposed to the α_(V)β₆ and/or the α_(V)β₈ integrin havereduced side-effects associated with inhibtion of the α_(V)β₆ and/or theα_(V)β₈ integrin. It is therefore another object of the presentinvention to provide compounds that are selective antagonists of α_(V)β₃and/or α_(V)β₅ as opposed to α_(V)β₆, and it is yet another object ofthe present invention to provide compounds that are selectiveantagonists of α_(V)β₃ and/or α_(V)β₅ as opposed to α_(V)β₈.

[0017] The present invention relates to a class of compounds representedby the Formula I

[0018] or a pharmaceutically acceptable salt thereof, wherein

[0019] is a 4-8 membered monocyclic ring or a 7-12 membered bicyclicring, which ring is optionally saturated or unsaturated; which ring isoptionally substituted with one or more substituent selected from thegroup consisting of alkyl, haloalkyl, aryl, heteroaryl, halogen,alkoxyalkyl, aminoalkyl, hydroxy, nitro, alkoxy, hydroxyalkyl,thioalkyl, amino, alkylamino, arylamino, alkylsulfonamide, acyl,acylamino, alkylsulfone, sulfonamide, allyl, alkenyl, methylenedioxy,ethylenedioxy, alkynyl, carboxamide, cyano, and —(CH₂)_(n) COR wherein nis 0-2 and R is hydroxy, alkoxy, alkyl or amino;

[0020] A¹ is a 5-9 membered monocyclic ring or 7-12 membered bicyclicheterocycle ring of the formula

[0021]  containing at least one nitrogen atom and optionally containing1 to 4 heteroatoms, selected from the group consisting of O, N, S, SO₂and CO; optionally saturated or unsaturated; optionally substituted byone or more R^(k) is selected from the group consisting of hydroxy,alkyl, alkoxy, alkoxyalkyl, thioalkyl, cyano, amino, alkylamino,haloalkyl, halogen, acylamino, sulfonamide and —COR wherein R ishydroxy, alkoxy, alkyl or amino;

[0022] or A¹ is

[0023] wherein Y¹ is selected from the group consisting of N—R², O, andS;

[0024] R² is selected from the group consisting of H; alkyl; aryl;hydroxy; alkoxy; cyano; amido; alkylcarbonyl; arylcarbonyl;alkoxycarbonyl; aryloxycarbonyl; haloalkylcarbonyl; haloalkoxycarbonyl;alkylthiocarbonyl; arylthiocarbonyl; acyloxymethoxycarbonyl;

[0025] R² taken together with R⁷ forms a 4-12 membered dinitrogencontaining heterocycle optionally substituted with one or moresubstituent selected from the group consisting of lower alkyl,thioalkyl, alkylamino, hydroxy, keto, alkoxy, halo, phenyl, amino,carboxyl or carboxyl ester;

[0026] or R² taken together with R⁷ forms a 4-12 membered heterocyclecontaining one or more heteroatom selected from O, N and S optionallyunsaturated;

[0027] or R² taken together with R⁷ forms a 5 membered heteroaromaticring fused with a aryl or heteroaryl ring;

[0028] R⁷ (when not taken together with R²) and R⁸ are independentlyselected from the group consisting of H; alkyl; aralkyl; amino;alkylamino; hydroxy; alkoxy; arylamino; amido, alkylcarbonyl,arylcarbonyl; alkoxycarbonyl; aryloxy; aryloxycarbonyl;haloalkylcarbonyl; haloalkoxycarbonyl; alkylthiocarbonyl;arylthiocarbonyl; acyloxymethoxycarbonyl; cycloalkyl; bicycloalkyl;aryl; acyl; benzoyl;

[0029] or NR⁷ and R⁸ taken together form a 4-12 membered mononitrogencontaining monocyclic or bicyclic ring optionally substituted with oneor more substituent selected from lower alkyl, carboxyl derivatives,aryl or hydroxy and wherein said ring optionally contains a heteroatomselected from the group consisting of O, N and S; R⁵ is selected fromthe group consisting of H, and alkyl;

[0030] or

[0031] A is

[0032] wherein Y is selected from the group consisting of alkyl;cycloalkyl; bicycloalkyl; aryl; monocyclic heterocycles;

[0033] Z₁ is selected from the group consisting of CH₂, CH₂O, O, NH,NR_(k), CO, S, SO, CH(OH), and SO₂, wherein R_(k) is selected from H orlower alkyl;

[0034] Z₂ is a 1-5 carbon linker optionally containing one or moreheteroatom selected from the group consisting of O, S and N;alternatively Z₁-Z₂ may further contain a carboxamide, sulfone, oxime,sulfonamide, alkenyl, alkynyl, or acyl group;

[0035] wherein the carbon and nitrogen atoms of Z₁-Z₂ are optionallysubstituted by alkyl, alkoxy, thioalkyl, alkylsulfone, aryl,alkoxyalkyl, hydroxy, alkylamino, heteroaryl, alkenyl, alkynyl,carboxyalkyl, halogen, haloalkyl or acylamino;

[0036] wherein Z₂-Z₁ is attached to

[0037] at the para or meta position relative to the X₁ substituent;

[0038] n is an integer 0, 1 or 2;

[0039] R^(c) is selected from the group consisting of hydrogen; alkyl;halogen, hydroxy, nitro, alkoxy, amino, haloalkyl, aryl, heteroaryl,alkoxyalkyl, aminoalkyl, hydroxyalkyl, thioalkyl, alkylamino, arylamino,alkylsulfonylamino, acyl, acylamino, sulfonyl, sulfonamide, allyl,alkenyl, methylenedioxy, ethylenedioxy, alkynyl, alkynylalkyl, carboxy,alkoxycarbonyl, carboxamido, cyano, and —(CH₂)_(n)—COR wherein n is 0-2and R is selected from hydroxy, alkoxy, alkyl and amino;

[0040] X₁ is selected from the group consisting of —O—, CO, SO₂, NR^(m)and (CHR^(p))_(q); wherein R^(m) is H or alkyl; R^(p) is H, alkyl,alkoxy or hydroxy and q is 0 or 1;

[0041] X₂ is selected from the group consisting of —CHR^(e)—, CO, SO₂,O, NR^(f) and S;

[0042] R^(e) is selected from the group consisting of H, alkyl, hydroxyand alkoxy; R^(f) is H or alkyl;

[0043] X or Y are independently selected from the group consisting of—CR^(g)— or —N— wherein R^(g) is selected from the group consisting ofH, alkyl, haloalkyl, fluoro, alkoxyalkyl, alkynyl, aryl, heteroaryl,aralkyl, alkylsulfone, heteroaralkyl, hydroxy, alkoxy, hydroxyalkyl, andcarboxyalkyl;

[0044] The group X—X₂—Y optionally contains a moiety selected from thegroup consisting of acyl, alkyl, amino, ether, thioether, sulfone, andolefin;

[0045] forms a 3-8 membered monocyclic ring system; or an 8-11 memberedbicyclic system; optionally saturated or unsaturated; the monocyclicring system optionally containing 1-2 heteroatoms selected from N, O andS; the bicyclic ring system optionally containing 1-4 heteroatomsselected from N, O, S or optionally containing the group such as SO₂ orCO); and optionally substituted with one or more substituent selectedfrom the group consisting of alkyl, halogen, cyano, carboalkoxy,haloalkyl, alkoxyalkyl, alkylsulfone, aryl, heteroaryl, aralkyl,heteroaralkyl or alkoxy;

[0046] R^(b) is X₃-R^(h) wherein X₃ is selected from the groupconsisting of O, S and NR^(j) wherein R^(h) and R^(j) are independentlyselected from the group consisting of H, alkyl, acyl, aryl, aralkyl andalkoxyalkyl; and

[0047] and ni s 0, 1 or 2.

[0048] It is another object of the invention to provide pharmaceuticalcompositions comprising compounds of the Formula I. Such compounds andcompositions are useful in selectively inhibiting or antagonizing theα_(V)β₃ and/or α_(V)β₅ integrin(s) and therefore in another embodimentthe present invention relates to a method of selectively inhibiting orantagonizing the α_(V)β₃ and/or α_(V)β₅ integrin(s). The inventionfurther involves treating or inhibiting pathological conditionsassociated therewith such as osteoporosis, humoral hypercalcemia ofmalignancy, Paget's disease, tumor metastasis, solid tumor growth(neoplasia), angiogenesis, including tumor angiogenesis, retinopathyincluding macular degeneration and diabetic retinopathy, arthritis,including rheumatoid arthritis, periodontal disease, psoriasis, smoothmuscle cell migration including restenosis or atherosclerosis in amammal in need of such treatment. Additionally, such pharmaceuticalagents are useful as antiviral agents, antifungals and antimicrobials.The compounds of the present invention may be used alone or incombination with other pharmaceutical agents.

DETAILED DESCRIPTION

[0049] The present invention relates to a class of compounds representedby the Formula I, described above.

[0050] In another embodiment of the present invention

[0051] is aryl or fused aryl optionally substituted by one or moresubstituent selected from lower alkyl, halogen, alkoxy, hydroxy, cyano,amino, alkylamino, dialkylamino or methylsulfonamide.

[0052] Another embodiments of

[0053] include the following heterocyclic ring systems containing atleast one nitrogen atom:

[0054] wherein R¹ is H, alkyl, alkoxyalkyl, acyl, hydroxyalkyl,haloalkyl, or alkoxycarbonyl; and Z is H, alkyl, alkoxy, hydroxy, amino,alkylamino, carboxyl, alkoxycarbonyl, hydroxyalkyl, halogen orhaloalkyl.

[0055] More specifically another embodiments include pyridylamino,imidazolylamino, oxazolylamino, thiazolylamino, pyrimidinylamino,quinoline, isoquinoline, morpholinopyridine, tetrahydronaphthyridine,tetrahydroquinoline, imidazopyridine, benzimidazole, pyridone orquinolone.

[0056] The following heteroaryls include the ring systems as describedabove.

[0057] For the pyridyl derived heterocycle, the substituents X₄ and X₅are preferentially H, alkyl, branched alkyl, alkylamino,alkoxyalkylamino, haloalkyl, thioalkyl, halogen, amino, alkoxy, aryloxy,alkoxyalkyl, hydroxy, cyano or acylamino groups. In another embodimentof the invention, the substituents X₄ and X₅ can be methyl, methoxy,amine, methylamine, dimethylamine, hydroxy, chloro, bromo, fluoro,trifluoromethyl and cyano. X₆ may preferentially be H, alkyl, halogen(F, Cl) alkoxy or haloalkyl. Alternately, the pyridyl ring can be fusedwith a 4-8 membered ring, optionally saturated or unsaturated. Someexamples of these ring systems include quinoline, azaquinoline,tetrahydroquinoline, imidazopyridine and the like. The monocyclic ringsystems such as imidazole, thiazole, oxazole, and the like, may containan amino or alkylamino substituent at any position within the ring.

[0058] In another embodiment of the present invention, when Z₁ ofFormula 1 is CO or SO₂, the linkage A¹-Z₂ of Formula I preferentiallyincludes the following heterocycle derived ring systems: pyridine,imidazole, thiazole, oxazole, benzimidazole, imidazopyridine and thelike.

[0059] Other preferred heterocycles formed by the A₁-Z₂ moiety of thepresent invention include

[0060] The substituent RC is preferably alkyl, halogen, alkoxy, hydroxy,cyano, a carboxyl derivative or methyl sulfonamide.

[0061] The invention further relates to pharmaceutical compositionscontaining therapeutically effective amounts of the compounds of FormulaI.

[0062] The invention also relates to a method of selectively inhibitingor antagonizing the α_(V)β₃ integrin and/or the α_(V)β₅ integrin andmore specifically relates to a method of inhibiting bone resorption,periodontal disease, osteoporosis, humoral hypercalcemia of malignancy,Paget's disease, tumor metastasis, solid tumor growth (neoplasia),angiogenesis, including tumor angiogenesis, retinopathy includingmacular degeneration and diabetic retinopathy, arthritis, includingrheumatoid arthritis, smooth muscle cell migration, including restenosisand atherosclerosis by administering a therapeutically effective amountof a compound of the Formula I to achieve such inhibition together witha pharmaceutically acceptable carrier.

[0063] The following is a list of definitions of various terms usedherein:

[0064] As used herein, the terms “alkyl” or “lower alkyl” refer to astraight chain or branched chain hydrocarbon radicals having from about1 to about 10 carbon atoms, and more preferably 1 to about 6 carbonatoms. Examples of such alkyl radicals are methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, neopentyl,hexyl, isohexyl, and the like.

[0065] As used herein the terms “alkenyl” or “lower alkenyl” refer tounsaturated acyclic hydrocarbon radicals containing at least one doublebond and 2 to about 6 carbon atoms, which carbon-carbon double bond mayhave either cis or trans geometry within the alkenyl moiety, relative togroups substituted on the double bond carbons. Examples of such groupsare ethenyl, propenyl, butenyl, isobutenyl, pentenyl, hexenyl and thelike.

[0066] As used herein the terms “alkynyl” or “lower alkynyl” refer toacyclic hydrocarbon radicals containing one or more triple bonds and 2to about 6 carbon atoms. Examples of such groups are ethynyl, propynyl,butynyl, pentynyl, hexynyl and the like.

[0067] The term “cycloalkyl” as used herein means saturated or partiallyunsaturated cyclic carbon radicals containing 3 to about 8 carbon atomsand more preferably 4 to about 6 carbon atoms. Examples of suchcycloalkyl radicals include cyclopropyl, cyclopropenyl, cyclobutyl,cyclopentyl, cyclohexyl, 2-cyclohexen-1-yl, and the like.

[0068] The term “aryl” as used herein denotes aromatic ring systemscomposed of one or more aromatic rings. Preferred aryl groups are thoseconsisting of one, two or three aromatic rings. The term embracesaromatic radicals such as phenyl, pyridyl, naphthyl, thiophene, furan,biphenyl and the like.

[0069] As used herein, the term “cyano” is represented by a radical ofthe

[0070] The terms “hydroxy” and “hydroxyl” as used herein are synonymousand are represented by a radical of the

[0071] The term “lower alkylene” or “alkylene” as used herein refers todivalent linear or branched saturated hydrocarbon radicals of 1 to about6 carbon atoms.

[0072] As used herein the term “alkoxy” refers to straight or branchedchain oxy containing radicals of the formula —OR²⁰, wherein R²⁰ is analkyl group as defined above. Examples of alkoxy groups encompassedinclude methoxy, ethoxy, n-propoxy, n-butoxy, isopropoxy, isobutoxy,sec-butoxy, t-butoxy and the like.

[0073] As used herein the terms “arylalkyl” or “aralkyl” refer to aradical of

[0074] the formula4 wherein R²¹ is aryl as defined above and R²² is analkylene as defined above. Examples of aralkyl groups include benzyl,pyridylmethyl, naphthylpropyl, phenethyl and the like.

[0075] As used herein the term “nitro” is represented by a radical ofthe

[0076] As used herein the term “halo” or “halogen” refers to bromo,chloro, fluoro or iodo.

[0077] As used herein the term “haloalkyl” refers to alkyl groups asdefined above substituted with one or more of the same or different halogroups at one or more carbon atom. Examples of haloalkyl groups includetrifluoromethyl, dichloroethyl, fluoropropyl and the like.

[0078] As used herein the term “carboxyl” or “carboxy” refers to aradical of the formula —COOH.

[0079] As used herein the term “carboxyl ester” refers to a radical ofthe formula —COOR²³ wherein R²³ is selected from the group consisting ofH, alkyl, aralkyl or aryl as defined above.

[0080] As used herein the term “carboxyl derivative” refers to a radicalof the formula

[0081] 6 wherein Y⁶ and Y⁷ are independently selected from the groupconsisting of O, N or S and R²³ is selected from the group consisting ofH, alkyl, aralkyl or aryl as defined above.

[0082] As used herein the term “amino” is represented by a radical ofthe formula —NH₂.

[0083] As used herein the term “alkylsulfonyl” or “alkylsulfone” refersto a radical of the

[0084] formula7 wherein R²⁴ is alkyl as defined above.

[0085] As used herein the term “alkylthio” refers to a radical of theformula —SR²⁴ wherein R is alkyl as defined above.

[0086] As used herein the term “sulfonic acid” refers to a radical ofthe

[0087] formula8 wherein R²⁵ is alkyl as defined above.

[0088] As used herein the term “sulfonamide” or “sulfonamido” refers toa radical of the

[0089] formula 9wherein R⁷ and R⁸ are as defined above.

[0090] As used herein the term “fused aryl” refers to an aromatic ringsuch as the aryl groups defined above fused to one or more phenyl rings.Embraced by the term “fused aryl” is the radical naphthyl and the like.

[0091] As used herein the terms “monocyclic heterocycle” or “monocyclicheterocyclic” refer to a monocyclic ring containing from 4 to about 12atoms, and more preferably from 5 to about 10 atoms, wherein 1 to 3 ofthe atoms are heteroatoms selected from the group consisting of oxygen,nitrogen and sulfur with the understanding that if two or more differentheteroatoms are present at least one of the heteroatoms must benitrogen. Representative of such monocyclic heterocycles are imidazole,furan, pyridine, oxazole, pyran, triazole, thiophene, pyrazole,thiazole, thiadiazole, and the like.

[0092] As used herein the term “fused monocyclic heterocycle” refers toa monocyclic heterocycle as defined above with a benzene fused thereto.Examples of such fused monocyclic heterocycles include benzofuran,benzopyran, benzodioxole, benzothiazole, benzothiophene, benzimidazoleand the like.

[0093] As used herein the term “methylenedioxy” refers to the

[0094] radical and the term “ethylenedioxy” refers to the radical 1011As used herein the term “4-12 membered dinitrogen containing heterocyclerefers to a radical of the formula

[0095] 12wherein m is an integer 1 to 1 and R¹⁹ is H, alkyl, aryl, oraralkyl and more preferably refers to 4-9 membered ring and includesrings such as imidazoline.

[0096] As used herein the term “5-membered optionally substitutedheteroaromatic ring” includes for example a radical of the formula

[0097] and “5-membered heteroaromatic ring fused with a phenyl” refersto such a “5-membered heteroaromatic ring” with a phenyl fused thereto.Representative of such 5-membered heteroaromatic rings fused with aphenyl is benzimidazole.

[0098] As used herein the term “bicycloalkyl” refers to a bicyclichydrocarbon radical containing 6 to about 12 carbon atoms which issaturated or partially unsaturated.

[0099] As used herein the term “acyl” refers to a radical of the formula

[0100] 13 wherein R²⁶ is alkyl, alkenyl, alkynyl, aryl or aralkyl andoptionally substituted thereon as defined above. Encompassed by suchradical are the groups acetyl, benzoyl and the like.

[0101] As used herein the term “thio” refers to a radical of the formula

[0102] As used herein the term “sulfonyl” refers to a radical of theformula

[0103] 15

[0104] wherein R²⁷ is alkyl, aryl or aralkyl as defined above.

[0105] As used herein the term “haloalkylthio” refers to a radical ofthe formula —S—R²⁸ wherein R²⁸ is haloalkyl as defined above.

[0106] As used herein the term “aryloxy” refers to a radical of theformula

[0107] 16 wherein R²⁹ is aryl as defined above.

[0108] As used herein the term “acylamino” refers to a radical of theformula

[0109] wherein R³⁰ is alkyl, aralkyl or aryl as defined above.

[0110] As used herein the term “amido” refers to a radical of theformula

[0111] As used herein the term “alkylamino” refers to a radical of theformula —NHR³² wherein R³² is alkyl as defined above.

[0112] As used herein the term “dialkylamino” refers to a radical of theformula —NR³³R³⁴ wherein R³³ and R³⁴ are the same or different alkylgroups as defined above.

[0113] As used herein the term “trifluoromethyl” refers to a radical ofthe formula

[0114] 18 As used herein the term “trifluoroalkoxy” refers to a radicalof the formula

[0115] wherein R³⁵ is a bond or an alkylene as defined above.

[0116] As used herein the term “alkylaminosulfonyl” or“alkylsulfonamide” refer to a radical of the formula

[0117] wherein R³⁶ is alkyl as defined above.

[0118] As used herein the term “alkylsulfonylamino” refers to a radicalof the formula

[0119] wherein R³⁶ is alkyl as defined above.

[0120] As used herein the term “trifluoromethylthio” refers to a radicalof the formula

[0121] As used herein the term “trifluoromethylsulfonyl” refers to aradical of the formula

[0122] As used herein the term “4-12 membered mono-nitrogen containingmonocyclic or bicyclic ring” refers to a saturated or partiallyunsaturated monocyclic or bicyclic ring of 4-12 atoms and morepreferably a ring of 4-9 atoms wherein one atom is nitrogen. Such ringsmay optionally contain additional heteroatoms selected from nitrogen,oxygen or sulfur. Included within this group are morpholine, piperidine,piperazine, thiomorpholine, pyrrolidine, proline, azacycloheptene andthe like.

[0123] As used herein the term “benzyl” refers to the radical

[0124] As used herein the term “phenethyl” refers to the radical

[0125] As used herein the term “4-12 membered mono-nitrogen containingmonosulfur or monooxygen containing heterocyclic ring” refers to a ringconsisting of 4 to 12 atoms and more preferably 4 to 9 atoms wherein atleast one atom is a nitrogen and at least one atom is oxygen or sulfur.Encompassed within this definition are rings such as thiazoline and thelike.

[0126] As used herein the term “alkylcarbonyl” refers to a radical ofthe formula

[0127] 26 wherein R⁵⁰ is alkyl as defined above.

[0128] As used herein the term “arylcarbonyl” refers to a radical of theformula

[0129] 27wherein R⁵⁰ is aryl as defined above.

[0130] As used herein the term “alkoxycarbonyl” refers to a radical ofthe formula

[0131] 28 wherein R⁵² is alkoxy as defined above.

[0132] As used herein the term “aryloxycarbonyl” refers to a radical ofthe formula

[0133] 29wherein R⁵¹ is aryl as defined above.

[0134] As used herein the term “haloalkylcarbonyl” refers to a radicalof the formula

[0135] 30 wherein R⁵³ is haloalkyl as defined above.

[0136] As used herein the term “haloalkoxycarbonyl” refers to a radicalof the formula

[0137] 31 wherein R⁵³ is haloalkyl as defined above.

[0138] As used herein the term “alkylthiocarbonyl” refers to a radicalof the formula

[0139] 32wherein R⁵⁰ is alkyl as defined above.

[0140] As used herein the term “arylthiocarbonyl” refers to a radical ofthe formula

[0141] 33wherein R⁵¹ is aryl as defined above.

[0142] As used herein the term “acyloxymethoxycarbonyl” refers to aradical of the formula

[0143] 34wherein R⁵⁴ is acyl as defined above.

[0144] As used herein the term “arylamino” refers to a radical of theformula R⁵¹—NH— wherein R⁵¹ is aryl as defined above.

[0145] As used herein the term “alkylamido” refers to a radical of theformula

[0146] 35wherein R⁵⁰ is alkyl as defined above.

[0147] As used herein the term “N,N-dialkylamido” refers to a radical ofthe formula

[0148] 36wherein R⁵⁰ is the same or different alkyl group as definedabove.

[0149] As used herein the term “acyloxy” refers to a radical of theformula R⁵⁵—O— wherein R⁵⁵ is acyl as defined above.

[0150] As used herein the term “alkenylene” refers to a linearhydrocarbon radical of 1 to about 8 carbon atoms containing at least onedouble bond.

[0151] As used herein the term “alkoxyalkyl” refers to a radical of theformula

[0152] wherein R⁵⁶ is alkoxy as defined above and R⁵⁷ is alkylene asdefined above.

[0153] As used herein the term “alkynylalkyl” refers to a radical of theformula R⁵⁹—R⁶⁰— wherein R⁵⁹ is alkynyl as defined as above and R⁶⁰ isalkylene as defined as above.

[0154] As used herein the term “alkynylene” refers to divalent alkynylradicals of 1 to about 6 carbon atoms.

[0155] As used herein the term “allyl” refers of a radical of theformula —CH₂CH═CH₂.

[0156] As used herein the term “aminoalkyl” refers to a radical of theformula H₂N—R⁶¹ wherein R⁶¹ is alkylene as defined above.

[0157] As used herein the term “benzoyl” refers to the aryl radicalC₆H₅—CO—.

[0158] As used herein the terms “carboxamide” or “carboxamido” refer toa radical of the formula —CO—NH₂.

[0159] As used herein the term “carboxyalkyl” refers to a radicalHOOC—R⁶²— wherein R⁶² is alkylene as defined as above.

[0160] As used herein the term “carboxylic acid” refers to the radical—COOH As used herein the term “ether” refers to a radical of the formulaR⁶⁰— wherein R⁶³ is selected from the group consisting of alkyl, aryland heteroaryl.

[0161] As used herein the term “haloalkylsulfonyl” refers to a radicalof the formula

[0162] wherein the R⁶⁴ is haloalkyl as defined above.

[0163] As used herein the term “heteroaryl” refers to an aryl radicalcontain at least one heteroatom.

[0164] As used herein the term “hydroxyalkyl” refers to a radical of theformula HO—R⁶⁵— wherein R⁶⁵ is alkylene as defined above.

[0165] As used herein the term “keto” refers to a carbonyl group joinedto 2 carbon atoms.

[0166] As used herein the term “lactone” refers to an anhydro cyclicester produced by intramolecular condensation of a hydroxy acid with theelimination of water.

[0167] As used herein the term “olefin” refers to an unsaturatedhydrocarbon radical of the type C_(n)H_(2n).

[0168] As used herein the term “sulfone” refers to a radical of theformula R⁶⁶—SO₂—.

[0169] As used herein the term “thioalkyl” refers to a radical of theformula R⁷⁷—S— wherein R⁷⁷ is alkyl as defined above.

[0170] As used herein the term “thioether” refers to a radical of theformula R⁷⁸—S— wherein R⁷⁷ is alkyl, aryl or heteroaryl.

[0171] As used herein the term “trifluoroalkyl” refers to an alkylradical as defined above substituted with three halo radicals as definedabove.

[0172] The term “composition” as used herein means a product whichresults from the mixing or combining of more than one element oringredient.

[0173] The term “pharmaceutically acceptable carrier”, as used hereinmeans a pharmaceutically acceptable material, composition or vehicle,such as a liquid or solid filler, diluent, excipient, solvent orencapsulating material, involved in carrying or transporting a chemicalagent.

[0174] The term “therapeutically effective amount” shall mean thatamount of drug or pharmaceutical agent that will elicit the biologicalor medical response of a tissue, system or animal that is being soughtby a researcher or clinician.

[0175] The following is a list of abbreviations and the correspondingmeanings as used interchangeably herein:

[0176]¹H-NMR=proton nuclear magnetic resonance

[0177] AcOH=acetic acid

[0178] Bn=benzyl

[0179] Boc=tert-butoxycarbonyl

[0180] Cat.=catalytic amount

[0181] CH₂Cl₂=dichloromethane

[0182] CH₃CN=acetonitrile

[0183] CHN analysis=carbon/hydrogen/nitrogen elemental analysis

[0184] DIBAL=diisobutylaluminum hydride

[0185] Dl water=deionized water

[0186] DMF=N,N-dimethylformamide

[0187] DMSO=dimethylsulfoxide

[0188] Et=ethyl

[0189] Etl=ethyliodide

[0190] Et₂O=diethyl ether

[0191] Et₃N=triethylamine

[0192] EtOAc=ethyl acetate

[0193] ETOH=ethanol

[0194] g=gram(s)

[0195] HPLC=high performance liquid chromatography

[0196] i-Pr=iso propyl

[0197] i-Prop=iso propyl

[0198] K₂CO₃=potassium carbonate

[0199] KOH=potassium hydroxide

[0200] L=Liter

[0201] LiOH=lithium hydroxide

[0202] Me=methyl

[0203] Mel=methyl iodide

[0204] MeOH=methanol

[0205] mg=milligram

[0206] MgSO₄=magnesium sulfate

[0207] ml=milliliter

[0208] mL=milliliter

[0209] MS=mass spectroscopy

[0210] MTBE=methyl t-butyl ether

[0211] N₂=nitrogen

[0212] NaH—sodium hydride

[0213] NaHCO₃=sodium bicarbonate

[0214] NaOH=sodium hydroxide

[0215] NaOMe=sodium methoxide

[0216] Na₂PO₄=sodium phosphate

[0217] Na₂SO₄=sodium sulfate

[0218] NH₄HCO₃=ammonium bicarbonate

[0219] NH₄ ⁺HCO2⁻=ammonium formate

[0220] NH₄OH=ammonium hydroxide

[0221] NMR=nuclear magnetic resonance

[0222] Pd=palladium

[0223] Pd/C=palladium on carbon

[0224] Ph=phenyl

[0225] Pt=platinum

[0226] Pt/C=platinum on carbon

[0227] RPHPLC=reverse phase high performance liquid chromatography

[0228] RT=room temperature

[0229] T-BOC=tert-butoxycarbonyl

[0230] TFA=trifluoroacetic acid

[0231] THF=tetrahydrofuran

[0232] Δ=heating the reaction mixture

[0233] The compounds as shown above can exist in various isomeric formsand all such isomeric forms are meant to be included. Tautomeric formsare also included as well as pharmaceutically acceptable salts of suchisomers and tautomers.

[0234] In the structures and formulas herein, a bond drawn across a bondof a ring can be to any available atom on the ring.

[0235] The term “pharmaceutically acceptable salt” refers to a saltprepared by contacting a compound of Formula I with an acid whose anionis generally considered suitable for human consumption. For use inmedicine, the salts of the compounds of this invention are non-toxic“pharmaceutically acceptable salts.” Salts encompassed within the term“pharmaceutically acceptable salts” refer to non-toxic salts of thecompounds of this invention which are generally prepared by reacting thefree base with a suitable organic or inorganic acid. Representativesalts include the following: benzenesulfonate, hydrobromide andhydrochloride. Furthermore, where the compounds of the invention carryan acidic moiety, suitable pharmaceutically acceptable salts thereof mayinclude alkali metal salts, e.g., sodium or potassium salts; alkalineearth metal salts, e.g., calcium or magnesium salts; and salts formedwith suitable organic ligands, e.g., quaternary ammonium salts. All ofthe pharmacologically acceptable salts may be prepared by conventionalmeans. (See Berge et al., J. Pharm. Sci., 66(1), 1-19 (1977) foradditional examples of pharmaceutically acceptable salts.) The compoundsof the present invention can have chiral centers and occur as racemates,racemic mixtures, diastereomeric mixtures, and as individualdiastereomers or enantiomers, with all isomeric forms included in thepresent invention. Therefore, where a compound is chiral, the separateenantiomers or diastereomers, substantially free of the other, areincluded within the scope of the present invention; further included areall mixtures of the enantiomers or diastereomers. Also included withinthe scope of the invention are polymorphs, or hydrates or othermodifiers of the compounds of invention.

[0236] The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds of this invention which arereadily convertible in vivo into the required compound. For example,prodrugs of a carboxylic acid may include an ester, an amide, or anortho-ester. Thus, in the methods of treatment of the present invention,the term “administering” shall encompass the treatment of the variousconditions described with the compound specifically disclosed or with acompound which may not be specifically disclosed, but which converts tothe compound of Formula I in vivo after administration to the patient.Conventional procedures for the selection and preparation of suitableprodrug derivatives are described, for example, in “Design of Prodrugs,”ed. H. Bundgaard, Elsevier, 1985, which is incorporated by referenceherein in its entirety. Metabolites of these compounds include activespecies produced upon introduction of compounds of this invention intothe biological milieu.

[0237] For the selective inhibition or antagonism of α_(V)β₃ and/orα_(V)β₅ integrins, compounds of the present invention may beadministered orally, parenterally, or by inhalation spray, or topicallyin unit dosage formulations containing conventional pharmaceuticallyacceptable carriers, adjuvants and vehicles. The term parenteral as usedherein includes, for example, subcutaneous, intravenous, intramuscular,intrasternal, transmuscular infusion techniques or intraperitonally.

[0238] The compounds of the present invention are administered by anysuitable route in the form of a pharmaceutical composition adapted tosuch a route, and in a dose effective for the treatment intended.Therapeutically effective doses of the compounds required to prevent orarrest the progress of or to treat the medical condition are readilyascertained by one of ordinary skill in the art using preclinical andclinical approaches familiar to the medicinal arts.

[0239] Accordingly, the present invention provides a method of treatingconditions mediated by selectively inhibiting or antagonizing theα_(V)β₃ and/or α_(V) β₅ cell surface receptor which method comprisesadministering a therapeutically effective amount of a compound selectedfrom the class of compounds depicted in the above formulas, wherein oneor more compound is administered in association with one or morenon-toxic, pharmaceutically acceptable carriers and/or diluents and/oradjuvants (collectively referred to herein as “carrier” materials) andif desired other active ingredients. More specifically, the presentinvention provides a method for selective antagonism of the α_(V)β₃and/or α_(V)β₅ cell surface receptors over α_(IIb)β₃ or α_(v)β₅ integrinreceptors. Most preferably the present invention provides a method forinhibiting bone resorption, treating osteoporosis, inhibiting humoralhypercalcemia of malignancy, treating Paget's disease, inhibiting tumormetastasis, inhibiting neoplasia (solid tumor growth), inhibitingangiogenesis including tumor angiogenesis, treating retinopathyincluding macular degeneration and diabetic retinopathy, inhibitingarthritis, psoriasis and periodontal disease, and inhibiting smoothmuscle cell migration including restenosis.

[0240] Based upon standard laboratory experimental techniques andprocedures well known and appreciated by those skilled in the art, aswell as comparisons with compounds of known usefulness, the compounds ofFormula I can be used in the treatment of patients suffering from theabove pathological conditions. One skilled in the art will recognizethat selection of the most appropriate compound of the invention iswithin the ability of one with ordinary skill in the art and will dependon a variety of factors including assessment of results obtained instandard assay and animal models.

[0241] Treatment of a patient afflicted with one of the pathologicalconditions comprises administering to such a patient an amount ofcompound of the Formula I which is therapeutically effective incontrolling the condition or in prolonging the survivability of thepatient beyond that expected in the absence of such treatment. As usedherein, the term “inhibition” of the condition refers to slowing,interrupting, arresting or stopping the condition and does notnecessarily indicate a total elimination of the condition. It isbelieved that prolonging the survivability of a patient, beyond being asignificant advantageous effect in and of itself, also indicates thatthe condition is beneficially controlled to some extent.

[0242] As stated previously, the compounds of the invention can be usedin a variety of biological, prophylactic or therapeutic areas. It iscontemplated that these compounds are useful in prevention or treatmentof any disease state or condition wherein the α_(V) β₃ and/or α_(V) β₅integrin plays a role.

[0243] The dosage regimen for the compounds and/or compositionscontaining the compounds is based on a variety of factors, including thetype, age, weight, sex and medical condition of the patient; theseverity of the condition; the route of administration; and the activityof the particular compound employed. Thus the dosage regimen may varywidely. Dosage levels of the order from about 0.01 mg to about 100 mgper kilogram of body weight per day are useful in the treatment of theabove-indicated conditions.

[0244] Oral dosages of the present invention, when used for theindicated effects, will range between about 0.01 mg per kg of bodyweight per day (mg/kg/day) to about 100 mg/kg/day, preferably 0.01 to 10mg/kg/day, and most preferably 0.1 to 1.0 mg/kg/day. For oraladministration, the compositions are preferably provided in the form oftablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0,25.0, 50.0, 100, 200 and 500 milligrams of the active ingredient for thesymptomatic adjustment of the dosage to the patient to be treated. Amedicament typically contains from about 0.01 mg to about 500 mg of theactive ingredient, preferably, from about 1 mg to about 100 mg of activeingredient. Intravenously, the most preferred doses will range fromabout 0.1 to about 10 mg/kg/minute during a constant rate infusion.Advantageously, compounds of the present invention may be administeredin a single daily dose, or the total daily dosage may be administered individed doses of two, three or four times daily. Furthermore, preferredcompounds for the present invention can be administered in intranasalform via topical use of suitable intranasal vehicles, or via transdermalroutes, using those forms of transdermal skin patches well known tothose of ordinary skill in the art. To be administered in the form of atransdermal delivery system, the dosage administration will, of course,be continuous rather than intermittant throughout the dosage regiment.

[0245] For administration to a mammal in need of such treatment, thecompounds in a therapeutically effective amount are ordinarily combinedwith one or more adjuvants appropriate to the indicated route ofadministration. The compounds may be admixed with lactose, sucrose,starch powder, cellulose esters of alkanoic acids, cellulose alkylesters, talc, stearic acid, magnesium stearate, magnesium oxide, sodiumand calcium salts of phosphoric and sulphuric acids, gelatin, acacia,sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, andtableted or encapsulated for convenient administration. Alternatively,the compounds may be dissolved in water, polyethylene glycol, propyleneglycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil,benzyl alcohol, sodium chloride, and/or various buffers. Other adjuvantsand modes of administration are well and widely known in thepharmaceutical art.

[0246] The pharmaceutical compositions useful in the present inventionmay be subjected to conventional pharmaceutical operations such assterilization and/or may contain conventional pharmaceutical adjuvantssuch as preservatives, stabilizers, wetting agents, emulsifiers,buffers, etc.

[0247] The general synthetic sequences for preparing the compoundsuseful in the present invention are outlined in SCHEMES 1-11. Both anexplanation of, and the actual procedures for, the various aspects ofthe present invention are described where appropriate. The followingSCHEMES and EXAMPLES are intended to be merely illustrative of thepresent invention, and not limiting thereof in either scope or spirit.Those with skill in the art will readily understand that knownvariations of the conditions and processes described in the SCHEMES andEXAMPLES can be used to synthesize the compounds of the presentinvention.

SCHEME 1

[0248] The compounds of FORMULA A₁₇ are generally prepared by reactingan intermediate of formula A₁₆ with a compound of the formula A₁₅. Forexample, when Z₃ is a (OH, SH or NHR), A₁₆ may be alkylated with A₁₅(Z₄=Br or OMs) using base such as (sodium hydride, potassium hydride)preferably in a solvent such as dimethylsulfoxide or DMF. Thesereactions may preferentially be carried at 0° C. to approximately 40° C.Alternately, when Z₃ and Z₄ are both OH, the ether formation to productA₁₇ may be accomplished by using Mitsunobu reaction. This reaction maypreferentially be carried out using triarylphosphine (such astriphenylphoshine) and dialkylazodicarboxylate (such as diethylazodicarboxylate, di-tert-butyl azodicarboxylate, di-iso-propylazodicarboxylate) in solvents such as DMF, methylene chloride, THF andthe like. When Z₃ carries a carboxylic acid or a sulfonic acid and Z₄ isan amine, standard coupling conditions may be used to synthesize thetarget A₁₇ compounds containing carboxamide (CONH) or the sulfonamide(SO₂NH).

[0249] Alternately, the compounds of FORMULA A₁₇ may be prepared bystarting with compounds of general formula A₁₈. For example, when Z₅ inA₁₈ is NH₂, cyclic or acyclic guanidino containing compounds of formulaA₁₇ may be synthesized by adopting the methodologies set forth in e.g.U.S. Pat. Nos. 5,852,210, and 5,773,646, hereby incorporated byreference. Similarly, compounds of formula A₁₈ (Z₅=NH₂) may be treatedwith appropriately substituted heteroaromatic system (such as2-halopyridine N-oxide) to give the target compound A₁₇. This reactionmay preferentially be carried out by refluxing the intermediate A₁₈ and2-halopyridine (such as 2-fluoropyridine, 2-chloropyridine N-oxide) insolvents such as tert-butyl alcohol, tert-amyl alcohol in the presenceof base (such as sodium bicarbonate, sodium carbonate, potassiumcarbonate, potassium bicarbonate).

[0250] When compounds of formula A₁₇ contain N-oxide (e.g., pyridineN-oxide), the deoxygenation is preferentially carried out using transferhydrogenation conditions (such as cyclohexene/Pd on carbon or ammoniumformate and Pd on carbon. When R^(b) is OR, the hydrolysis of theresulting ester may be carried out using an aqueous base such as sodiumhydroxide, lithium hydroxide, potassium hydroxide and using co-solventsas methanol, ethanol or THF.

[0251] Compounds of the general formula A₁₅, A₁₆, A₁₈ may be prepared bymethodologies discussed in SCHEMES 2-11 which follow.

SCHEME 2

[0252] Compounds of the FORMULA A₄ may be prepared by starting with asubstituted cinnamyl alcohol of formula A₁. The compounds of formula A₁may be synthesized from the corresponding cinnamic acid or its esters byreduction with e.g.; DIBAL, lithium borohydride or the like.Cyclopropanation of A₁ using Simmons-Smith reaction gives thecyclopropyl containing intermediate A₂. The conditions described in eg.; Chem. Letts; 61-64,1992; Bull. Chem. Soc., Japan, 70, 207-217,1997and the references cited therein may be used for this reaction.Oxidation of resulting alcohol (using e.g., oxalyl chloride, DMSO)followed by homologation, as described in Tetrahedron Lett 25,4549-4552,1984, gives the enol ether A₃. Hydrolysis of the enol ether A₃with e.g., 1N HCl and oxidation of the resulting aldehyde with e.g.;silver nitrate gives the acid A₄. The acid may be esterified using analcohol (such as ethanol) and an acid catalyst. The intermediate A₄ isprocessed to the compounds of Formula I by synthetic transformations asoutlined in SCHEME 1.

SCHEME 3

[0253] Compounds of FORMULA A₇ containing a cyclopentyl ring may beprepared by starting with readily accessible intermediate A₅ by reactionof 2-chloro-cyclopentanone with aryl magnesium halide (see e.g, Can. J.Chem., 70,1274-1280, 1992; Chem. Pharm. Bull., 34, 3599,1986). UsingWittig or Horner-Emmons reaction, the compound A₅ is converted to theolefin containing intermediate A₆. This reaction is carried out usingtrialkyl phosphonoacetate (such as triethyl phosphonoacetate, trimethylphosphonoacetate) and a base (e.g., sodium hydride, sodium methoxide,sodium ethoxide). This reaction is generally done at low temperature(0-30° C.) and using THF, DMF as solvents. The isomeric mixtures ofolefin containing compounds are hydrogenated using e.g, Pd on carbon orPt on carbon as catalyst. This reduction is carried under pressure ofhydrogen (preferably 5-60 psi) to give the desired intermediate A₇. Theintermediate A₇ is processed to the compounds of Formula I by synthetictransformations outlined in SCHEME 1.

SCHEME 4

[0254] Compounds of FORMULA I with a cyclopentyl ring substituted in a1,3-arrangement are prepared by starting with readily accessibleintermediate A₈. The methodology described in e.g.; J. Am. Chem. Soc.67, 286, 1945; or J. Med. Chem., 33, 2828, 1990 may be used tosynthesize A₈ with a variety of substituents on the aryl ring.Elaboration of carbonyl functionality of A₈ to intermediate A₁₀ may beaccomplished in a similar manner as described in SCHEME 3. Theintermediate A₈ is processed to the compounds of Formula I by synthetictransformations outlined in SCHEME 1.

SCHEME 5

[0255] Compounds of FORMULA I, wherein X₁ is CH₂ are prepared startingwith commercially accessible intermediate A₁₁. Reduction of thecarboxylic acid functionality in A₁₁ with e g; diborane or lithiumaluminum hydride gives the hydroxymethyl derivative which may beelaborated to CH₂CO₂R functionality using the methodology elaborated inEXAMPLE 1. Demethylation of the intermediate with a boron trihalide suchas boron tribromide, boron trichloride gives the demethylatedintermediates A₁₃ which is processed to the compounds of Formula I bysynthetic transformations as outlined in SCHEME 1.

SCHEME 6

[0256] The compounds of FORMULA I, wherein A¹ is substituted pyridyl maybe prepared by adopting the general synthetic SCHEME 6. For example,reaction of substituted 2-halopyridine N-oxide (such as A_(19a)-A_(19d))with e.g. 3-aminopropanol gives the intermediates A_(20a)-A_(20d). Thisreaction may preferentially be carried out by refluxing the intermediate2-halopyridine N-oxide (such as 2-chloropyridine N-oxide) in solventssuch as tert-butyl alcohol, tert-amyl alcohol in the presence of base(such as sodium bicarbonate, sodium carbonate, potassium carbonate,potassium bicarbonate). The preparative conditions described in WO99/15508 (PCT US 98/19466) may be used for this transformation.

[0257] Coupling of the intermediates A_(20a)-A_(20d) with A₁₆ usingMitsunobu reaction gives the compounds containing the ether link. Thisreaction may preferentially be carried out using triarylphosphine (suchas triphenylphoshine) and dialkylazodicarboxylate (such as diethylazodicarboxylate, di-tert-butyl azodicarboxylate, di-iso-propylazodicarboxylate) in solvents such as DMF, methylene chloride, or THF.N-Deoxygenation of resulting intermediates followed by hydrolysis of theester gives the compounds (A_(21a)-A_(21d)).

[0258] Reduction of the N-oxide bond may be accomplished using e.g.,transfer hydrogenation (cyclohexene/Pd on carbon) or ammonium formateand Pd on carbon. The nitro group in A_(21d) may be hydrogenated usingPd on carbon or Pt on carbon as catalysts. This transformation may becarried out using solvents such as methanol, ethanol or THF. Thehydrolysis of the ester group may be carried using aqueous base (such assodium hydroxide, lithium hydroxide or potassium hydroxide) in solventssuch as methanol, ethanol and THF.

[0259] Compounds of Formula I containing a heterocycle other thanpyridyl can also be prepared using the methodology of SCHEME 6. Forexample reaction of 2-bromopyrimidine or 1-chloroisoquinoline N-oxidewith 3-amino-propanol gives the analogous intermediates as obtained inSTEP 1 of SCHEME 6. The resulting intermediates could be elaborated asin SCHEME 6 to give the pyrimidine and isoquinoline containing compoundsof FORMULA I.

SCHEME 7

[0260] Compounds of FORMULA I containing 6-amino substituents may beprepared as shown in SCHEME 7. The intermediate A_(22b) can be preparedas described in J. Med. Chem 43, 22, 2000. Boc-protected2-amino-6-picoline (A_(22a1)) or its ethylated derivative (A_(22c1)) areelaborated to A_(22a) and A_(22c) as shown for case A_(22b) in the abovepublication. The ethylated intermediate A_(22c1) may be prepared fromA_(22a1) by alkylation using e.g.; Etl and a base such as potassiumcarbonate, cesium carbonate. This reaction may preferentially be carriedout in polar solvents such as dimethylformamide, or dimethylacetamide.Mitsunobu reaction of A₁₆, gives the compounds containing the phenolether. Removal of Boc group using e.g., trifluoroacetic acid, insolvents such as dichloromethane, followed by hydrolysis of the estergroup as discussed in SCHEME 6 above gives the compounds(A_(23a)-A_(23c)).

SCHEME 8

[0261] The cyclopropyl compounds having a substituent at the β-positionto the carboxylic acid can be prepared as shown in scheme above. Forexample, Horner Emmons reaction of 4-substituted benzaldehyde withtriethyl phosphonoalkanoate (A) gives the olefin containingintermediate. This reaction may be carried out in the presence of a base(e.g.; NaH, sodium tert-butoxide and the like) in a solvent such as THFor DMF. The methodology described in e.g.; Synthesis 661-664 (1986) andSynth. Communication 18, 1349-1362 (1988) may be used to synthesizeintermediate (A₂). The sequence of reactions described in EXAMPLE 1 canbe used to accomplish the synthesis of the target compounds (B₁ and B₂).

SCHEME 9

[0262] The target compounds of FORMULA 1 with variations inheteroarylamine A¹can be prepared following the reaction sequence shownin SCHEME 9 above. The reductive amination of arylamine (A₂₄) with analiphatic aidehyde (A₂₅) gives the intermediate A₂₆ containing thealiphatic chain. This reaction may preferentially be carried out byusing sodium triacetoxyborohydride, sodium cyanoborohydride or sodiumborohydride as reducing agent and using methyene chloride, ethyl alcoholor tetrahydrofuran as solvent. Commercially accessible heteroarylaminesuch as 2-amnopyridine could be used directly. In certain cases,protected heteroaryls such as imidazole and pyrazole derived amines maybe used as shown above. Desilylation of A₂₆ can be accomplished usingreagents such as cesium fluoride, potassium fluoride and the like. Thegenerated alcohol A₂₇ could be reacted with the substituted phenol asshown in number of examples (for example 4). The trityl, Cbz or otherprotected groups can easily be removed by methodologies known inliterature.

SCHEME 10

[0263] Compounds of FORMULA 1 containing 6-aminopyridyl system may beprepared as shown in scheme 10. The intermediate 1 can be prepared asdescribed in J. Med. Chem 43, 22, 2000. The hydroxyl group in 1 can beprotected as silyl ether using e.g; ter-butyldimethylsilyl chloride andimidazole. The reaction of generated intermediate with a base such as(sodium hydride in DMF) and the alkyl halide gives the intermediate 2after deprotection of the silyl ether. Mitsunobu reaction of 2 withphenolic intermediate A₃ described in scheme 8 above, gives thecompounds containing the phenol ether. Removal of Boc group using e.g.,trifluoroacetic acid in solvents such as dichloromethane, followed byhydrolysis of the ester group as discussed in scheme 6 above gives thetarget compounds 4.

SCHEME 11

[0264] The compounds of FORMULA 1 with substituents in phenyl ring A canbe synthesized as shown in the above scheme. For example, Horner Emmonsreaction of 4-substituted benzaldehyde with triethyl phosphonoacetategives the olefin containing intermediate. This reaction may be carriedout in the presence of a base (e.g.; NaH, sodium tert-butoxide and thelike) in a solvent such as THF or DMF. The intermediate can behomologated using the methodology developed by Kowalski and described inJ. Am. Chem Soc., 108,1429-30, 1985 and J. Org. Chem 57, 7194, 7208,1992. The reaction conditions described in Step 3, of EXAMPLE 1 can beused to give the cyclopropyl containing intermediate. Elaboration ofthis intermediate involving demethylation, Mitsunobu reaction,deoxygenation and hydrolysis of ester gives the target compound. Theexperimental conditions described in Steps 4-7, of SCHEME 2 can be usedto achieve the synthesis of target compound.

[0265] Alternately, the cinnamic acid derivative 2 may be elaborated tothe cyclopropyl containing intermediate 3 and the target 4 following themethodology shown in example 9.

EXAMPLE A 2-[3-hydroxy-1-propylamino]pyridine-N-oxide

[0266]

[0267] A mixture of 2-chloropyridine-N-oxide (16.6 g, 100 mmoles),3-amino-1-propanol (15.3 ml, 200 mmoles), NaHCO₃ (42 g, 0.5 mole), andtert-amyl alcohol (100 ml ) was heated to reflux. After 23 hours, thereaction was cooled, diluted with CH₂Cl₂ (300 ml ), and filtered toremove insoluble materials. The filtrate was concentrated to afford abrown oil. The oil was dried under vacuum overnight. Ether (100 ml) wasadded to give a brown solid. The ether was decanted and the solid waswashed further with ether/acetonitrile (3/1). The resulting solid washeated at 67° C. under vacuum to give the desired product (13.5 g). ¹HNMR was consistent with the proposed structure.

EXAMPLE 1 2-[4-[3-(2-pyridinylamino)propoxy]phenyl]cyclopropaneaceticacid, mono(trifluoracetate)

[0268]

[0269] Step 1

[0270] To a solution of trans-4-hydroxy cinnamic acid (16.4 g) andimidazole (20.4 g) in DMF (150 mL) was added a solution oft-butyldimethyl silyl chloride (31.7 g) in DMF (50 mL) in one portion atroom temperature. The reaction was stirred for 1 hour and then thesolvent was removed in vacuo. The residual oil was partitioned betweenether and 5% aqueous citric acid. The organic portion was washed withwater, and brine and then dried over MgSO₄ and concentrated to afford acolorless oil (41.6 g) which was used without further purification. The¹H NMR was consistent with the proposed structure.

[0271] Step 2

[0272] A solution of the product from Step 1 (30.0 g) in ether (250 mL)was placed in a flame dried flask under N₂ and chilled to zero degrees.A solution of 250 mL diisobutyl aluminum hydride (200 mL) (1.0 M in THF)was added dropwise over 1 hour and stirring was continued for anadditional 1 hour at zero degrees after the addition was completed. Thereaction was then carefully quenched with saturated ammonium chloridesolution (200 mL) with vigorous stirring. The mixture was stirred for 2hours, filtered, washed with ether and the layers separated, and theorganic portion concentrated. The residual oil was purified in a silicagel column eluting with 25% ethyl acetate/hexane to afford a viscouscolorless oil (6.6 g). The ¹H NMR was consistent with the proposedstructure.

[0273] Step 3

[0274] In a flame dried flask under nitrogen was placed a solution ofdiiodo-methane (2.14 g) and methylene chloride (10 mL). The solution waschilled to 0° and diethyl zinc (1.0M solution in hexane; 4.0 mL) wasadded rapidly. The solution was stirred at zero degrees for 15 minutesand then a solution of the product from Step 2 (1.0 g) in 5 mL ofmethylene chloride was added dropwise. The reaction was stirred for 90minutes while allowing to warm to room temperature and then quenchedwith water (5 mL) and partitioned between 0.25N HCl and ethyl acetate.The aqueous portion was extracted with additional solvent and thecombined organic extracts were washed with brine, dried over MgSO₄,concentrated and the residue purified on a silica gel column elutingwith 25% ethyl acetate/hexane to afford a colorless heavy liquid (510mg). The ¹H NMR was consistent with the proposed structure.

[0275] Step 4

[0276] A solution of of oxalyl chloride (1.71 g) in methylene chloride(25 mL) was cooled to −60° C. under nitrogen and a solution of DMSO(2.11 g) in CH₂Cl₂ (5 mL) was added dropwise and stirring was continuedfor two minutes. Next, a solution of the product from Step 3 (3.3 g) inCH₂Cl₂ (5 mL) was added dropwise over 5 minutes and the resultantmixture was stirred for 15 minutes at −60° C. After this period,triethylamine (6.07 g) was added rapidly and the mixture stirred at −60°C. for an additional 5 minutes before being allowed to warm to roomtemperature. The reaction was diluted with water (50 mL) and extractedseveral times with methylene chloride. The combined organic extractswere then successively washed with 1% HCl solution, 5% sodium carbonatesolution and brine. After drying over MgSO₄ and concentrating, theresidue was purified on a silica gel column eluting with 25% ethylacetate/hexane to afford a light yellow liquid (2.85 g). The ¹H NMR wasconsistent with the proposed structure.

[0277] Step 5

[0278] To a suspension of methoxymethyl triphenylphosphonium chloride(5.14 g) in THF (15 mL) was added lithium bis (trimethylsilyl) amide (15mL, 1.0 M solution in THF) dropwise at zero degrees under nitrogen.After 15 minutes a solution of the product from Step 4 (2.8 g) in THF(20 mL) was added dropwise and stirring continued for 15 minutes. Thereaction was then partitioned between ether and water and the layersseparated. The aqueous portion was extracted with additional ether andthe combined organic extracts were washed with brine, dried over Na₂SO₄and concentrated. The residue was purified on a silica gel columneluting with 10% ethyl acetate/hexane to afford a liquid (1.78 g). ¹HNMR was consistent with the proposed structure.

[0279] Step 6

[0280] A solution of the product from Step 5 (1.75 g), acetonitrile (45mL) and 1 N HCl (12 mL) was warmed to 64° C. for 15 hours undernitrogen. The reaction was then cooled and partitioned between ether andsaturated sodium bicarbonate solution. The aqueous portion was extractedthoroughly with additional ether and the combined organic extracts werewashed with brine, dried over Na₂SO₄, and concentrated. The residue waspurified on a silica gel column eluting with 35% ethyl acetate/hexane toafford a viscous oil (491 mg). ¹H NMR spectra was consistent with theproposed structure.

[0281] Step 7

[0282] To a suspension of the product from Step 6 (490 mg) in water (5mL) was successively added a solution of silver nitrate (1.0 g) in water(5 mL) and sodium hydroxide(480 mg) in water (5 mL) at room temperature.The black mixture was stirred for 1 hour and then filtered through a padof celite. The filtrate was acidified with 1N HCl and extracted withethyl acetate. The combined organic extracts were dried over Na₂SO₄ andconcentrated to a brown residue which was treated with a 1:1 mixture ofethanol and 4N HCl/dioxane (30 mL) at room temperature for 18 hours. Thereaction was concentrated and the residue was purified on a silica gelcolumn eluting with 25% ethyl acetate/hexane to afford a golden oil (226mg). ¹H NMR spectra was consistent with the proposed structure.

[0283] Step 8

[0284] To a solution of the product from Step 7 (220 mg) in DMF (3 mL)under nitrogen was added 2-[3-hydroxy-1-propyl)amino] pyridine-N-oxide(Example A) and triphenylphosphine (315 mg). The solution was stirred atroom temperature for several minutes and then a solution of diethylazodicarboxylate (209 mg) in DMF (2 mL) was added dropwise. The reactionwas stirred for 18 hours and the solvent was removed in vacuo. Theresidue was purified on a silica gel column eluting with 94% CH₂Cl₂-5%CH₃OH-1% NH₄OH to afford a viscous golden oil (125 mg). ¹H NMR wasconsistent with the proposed structure.

[0285] Step 9

[0286] A mixture of the product from Step 8 (120 mg), 10% Pd on carbon(125 mg), cyclohexene (1.0 mL) and isopropanol (10 mL) was refluxed for3 hours. The reaction mixture was cooled, filtered through a pad ofcelite and washed with excess isopropanol. The filtrate was concentratedand the residue was purified on a silica gel column eluting with 97%CH₂Cl₂-2.5% CH₃OH and 0.5% NH₄OH to afford a colorless oil (74 mg). ¹HNMR was consistent with the proposed structure.

[0287] Step 10

[0288] A solution of the product from Step 9 (70 mg) in methanol (5 mL)and 1 N sodium hydroxide (5 mL) was stirred at room temperature for 18hours. The reaction mixture was quenched with trifluoroacetic acid (1mL) and concentrated. The residue was purified on a reverse place HPLCusing acetonitrile/water (0.5%.TFA) gradient to give the desired productas a viscous oil (36 mg). Elemental analysis: calcd. for C₁₉H₂₂N₂O₃.TFAC, 57.27;H, 5.26; N, 6.36; Found: C, 57.99;H, 5.44; N, 6.27; ¹H NMR wasconsistent with the proposed structure.

EXAMPLE 2 2-[4-[3-(2-pyridinylamino)propoxy]phenyl]cyclopentaneaceticAcid

[0289]

[0290] Step 1

[0291] In a flame dried flask under N₂ was placed a solution of2-chlorocyclopentanone (10.0 g) in diethyl ether (50 mL). While stirringat room temperature, 4-methoxyphenylmagnesium bromide (170 mL; 0.5 Msolution in THF) was added dropwise. An exothermal reaction ensued andstirring was continued for an additional 30 minutes after the additionwas completed. The reaction was quenched with 1N HCl (150 mL) and thelayers were separated. The aqueous portion was extracted with ethylacetate and then the combined organic portions were washed with waterand brine and then dried (Na₂SO₄) and concentrated. The residue waspurified on a silica gel column eluting with 25% ethyl acetate/hexane toafford a dark oil (4.1 g). ¹H NMR was consistent with the proposedstructure.

[0292] Step 2

[0293] In a flame dried flask under N₂ was suspended sodium hydride (310mg, 60% dispersion) in THF (10 mL). A solution oftriethylphosphonoacetate (1.74 g) in THF (5 mL) was added dropwise andthe reaction was allowed to stir at room temperature for 30 minutes. Asolution of the product from Step 1 (1.0 g) in THF (5 mL) was added inone portion and the reaction brought to reflux for 1 hour. The reactionwas cooled and partitioned between 1 N HCl and ethyl acetate. Theaqueous portion was extracted with additional ethyl acetate and thecombined organic extracts were washed with water, brine, dried (Na₂SO₄),and concentrated. The residue was purified on a silica gel columneluting with 20% ethyl acetate/hexane to afford a liquid (800 mg). ¹HNMR was consistent with the proposed structure.

[0294] Step 3

[0295] A solution of the product from Step 2 (800 mg) in ethanol wasshaken in a Parr hydrogenation apparatus with 5% Pd/C under 60 psihydrogen pressure at room temperature for 3 hours. The reaction mixturewas then filtered and concentrated and the residual oil (691 mg) wasused without further purification in the next step. ¹H NMR wasconsistent with the proposed structure.

[0296] Step 4

[0297] To a solution of the product from Step 3 (2.70 g) in methylenechloride (15 mL) was added boron tribromide (25 mL, 1.0 M solution inCH₂Cl₂) over 10 minutes at room temperature. After stirring at roomtemperature for 1 hour, the reaction was quenched with ethanol and thenconcentrated. The residue was partitioned between ethyl acetate and 10%sodium bicarbonate solution. The aqueous portion was extracted withadditional solvent and the combined organic solvents were washed withbrine, dried over Na₂SO₄, concentrated, and the residue purified on asilica gel column eluting with 25% ethyl acetate/hexane to afford agolden oil (1.74 g). ¹H NMR was consistent with the proposed structure.

[0298] Step 5

[0299] The title compound produced in Step 5 was prepared from theproduct described in Step 4 (1.60 g) using the same procedure asdescribed in Step 8 of Example 1. The crude product was purified on asilica gel column eluting with 95% CH₂Cl₂-4% CH₃OH-1%NH₄OH to afford agolden oil (2.08 g). ¹H NMR was consistent with the proposed structure.

[0300] Step 6

[0301] The compound produced in Step 6 was prepared from the productdescribed in Step 5 (2.0 g) using the same procedure as described inStep 9 of Example 1. The crude product was purified on a silica gelcolumn eluting with 97% CH₂Cl₂-2% CH₃OH-1% NH₄OH to afford a viscous oil(1.2 g). ¹H NMR was consistent with the proposed structure.

[0302] Step 7

[0303] The title compound was prepared from the product described inStep 6 (500 mg) using the same procedure as described in Step 10 ofExample 1. The crude product was purified in similar fashion to afford aviscous colorless glass (272 mg). Elemental analysis: Calculated forC₂₁H₂₆N₂O_(3.)1.5 TFA. 0.25H₂O: C, 54.39;H, 5.33; N, 5.29; Found: C,54.35;H, 5.46; N, 5.31. ¹H-NMR was consistent with the proposedstructure.

EXAMPLE 3 3-[4-[3-(2-pyridinylamino)propoxy]phenyl]cyclopentaneaceticAcid

[0304]

[0305] Step 1

[0306] The starting material was prepared according to the procedure ofWilds and Johnson, J.A.C.S., 67,286-290, 1945. The compound was preparedfrom 3-(4-methoxyphenyl) cyclopentenone (2.5 g) using the same procedureas described in Step 2 of Example 2. The crude product was purified on asilica gel column eluting with 30% ethyl acetate/hexane to afford anorange solid (1.53 g). ¹H NMR was consistent with the proposedstructure.

[0307] Step 2

[0308] A solution of the product from Step 1 (1.5 g) in ethanol wasshaken in a Parr hydrogenation apparatus with 4% Pd/C under 5 psihydrogen pressure at room temperature for 8 hours. The reaction mixturewas filtered and concentrated and the crude product was purified on asilica gel column eluting with 25% ethyl acetate/hexane to afford aliquid (1.35 g). ¹H NMR was consistent with the proposed structure.

[0309] Step 3

[0310] The compound produced in Step 3 was prepared from the productdescribed in Step 2 (1.3 g) using the same procedure described in Step 4of Example 2. The crude product was purified on a silica gel columneluting with 30% ethyl acetate/Hexane to afford a liquid (1.22 g). ¹HNMR was consistent with the proposed structure.

[0311] Step 4

[0312] The compound produced in Step 4 was prepared from the productdescribed in Step 3 (600 mg) using the same procedure described in Step8 of Example 1. The crude product was purified on a silica gel columneluting with 96.5% CH₂Cl₂-3.0% CH₃OH-0.5% NH₄OH to afford a golden oil(606 mg). ¹H NMR was consistent with the proposed structure.

[0313] Step 5

[0314] The compound produced in Step 5 was prepared from the productdescribed in Step 4 (595 mg) using the same procedure described in Step9 of Example 1. The crude product was purified on a silica gel columneluting with 97.5% CH₂Cl₂-2.0% CH₃OH-0.5% NH₄OH to afford a semi solid(320 mg). ¹H NMR was consistent with the proposed structure.

[0315] Step 6

[0316] The title compound was prepared from the product described inStep 5 (310 mg) using the same procedure described in Step 10 ofExample 1. The crude product was purified in similar fashion to afford awhite solid (191 mg). Analysis: Calculated for C₂₁H₂₆N₂O_(3.)1.0 TFA: C,58.97;H, 5.81; N, 5.98; Found: C, 58.70;H, 5.81: N, 5.92. ¹H NMR wasconsistent with the proposed structure.

EXAMPLE 42,2-difluoro-3-[4-[3-(2-pyridinylamino)propoxy]phenyl]cyclopropaneaceticAcid

[0317]

[0318] Step 1

[0319] A solution of 4-methoxy trans cinnamic acid (20 g) in absoluteethanol (300 ml) and 4N HCl/dioxane (100 ml) was stirred at roomtemperature for 16 hours. The solution was concentrated and the residuewas purified on a silica gel column eluting with 25% ethylacetate/hexane to afford a low melting solid (17.5 g) which solidifiedto a glass upon standing at room temperature. The ¹H NMR was consistentwith the proposed structure.

[0320] Step 2

[0321] In a flame dried flask under nitrogen was placed a solution of2,2,6,6-tetramethylpiperidine (24.66 g) in THF (150 ml) and chilled to00. A solution of n-BuLi (2.5 M in hexane; 64 ml) was added dropwiseover 10 minutes and stirring was continued for an additional 15 minutesafter the addition was completed. This solution was then added dropwiseto a solution of dibromomethane (27.8 g) in THF (150 ml) in anotherflame dried flask under nitrogen at −700. After 5 minutes a solution ofthe ester (10.0 g) from Step 1 in THF (50 ml) was added dropwise over 5minutes and 10 minutes later additional 2,2,6,6-tetramethylpiperidine(6.85 g) was added followed by n-BuLi (2.5 M in hexane; 155 ml)dropwise. The cooling bath was then replaced by a water bath at roomtemperature and after the reaction was stirred for 15 minutes it waspoured into an ice cold acidic ethanol solution (prepared from 125 ml ofacetyl chloride in 625 ml of ethanol). The mixture was then extractedseveral times with ether and the combined extracts were washed with 10%sulfuric acid, 5% sodium bicarbonate solution, brine and dried (Na₂SO₄).The filtered solution was concentrated and the residue was purified on asilica gel column eluting with 20% ethyl acetate/hexane to afford a darkred oil (2.46 g). The ¹H NMR was consistent with the proposed structure.

[0322] Step 3

[0323] A mixture of the ester (2.4 g) from Step 2, sodiumchlorodifluoroacetate (10.7 g) and diglyme (90 ml) was refluxed under N₂for 16 hours. The reaction was cooled and partitioned between ethylacetate and water. The aqueous portion was extracted with additionalethyl acetate and the combined organic extracts were washed with water,brine, and dried (Na₂SO₄). The filtered solution was concentrated andthe residue was purified on a silica gel column eluting with 20% ethylacetate/hexane to afford a golden oil (1.23 g). The ¹H NMR wasconsistent with the proposed structure.

[0324] Step 4

[0325] A solution of the ester (1.2 g) from Step 3 in methylene chloride(25 ml) was chilled to 0° under N₂ and treated dropwise with borontribromide (1.0 M in methylene chloride; 10 ml). The reaction wasstirred for 30 minutes while allowing to warm to room temperature. Thereaction was then carefully quenched with ethanol (10 ml), stirred for15 minutes and concentrated. The reaction was partitioned between ethylacetate and 10% sodium bicarbonate solution. The aqueous portion wasextracted with additional ethyl acetate and the combined organicextracts were washed with brine and dried (Na₂SO₄). The filteredsolution was concentrated and the residue was purified on a silica gelcolumn eluting with 30% ethyl acetate/hexane to afford a light yellowsolid (863 mg). The ¹H NMR was consistent with the proposed structure.

[0326] Step 5

[0327] To a solution of the product from Step 4 (1.0 g) in THF (25 ml)under nitrogen was added 2-[(3-hydroxy-1-propyl)amino] pyridine-N-oxide(841 mg) and triphenylphosphine (1.31 g). The solution was stirred atroom temperature for several minutes and then a solution ofdiethylazodicarboxylate (871 mg) in THF (15 ml) was added dropwise. Thereaction was stirred for 18 hours and the solvent was removed in vacuo.The residue was purified on a silica gel column eluting with 97%CH₂Cl₂-2.5% CH₃OH-0.5% NH₄OH to afford a golden oil (1.02 g). The ¹H NMRwas consistent with the proposed structure.

[0328] Step 6

[0329] A mixture of the product of Step 5 (500 mg), 10% Pd on carbon(128 mg), ammonium formate (543 mg) and methanol (10 ml) was stirred atroom temperature for 20 hours. The reaction mixture was concentrated andthe residue was purified on a silica gel column eluting with 97.5%CH₂Cl₂-2% CH₃OH-0.5% NH₄OH to afford a viscous oil (189 mg). The ¹H NMRwas consistent with the proposed structure.

[0330] Step 7

[0331] A solution of the product from Step 6 (180 mg) in methanol (5 ml)and 1N sodium hydroxide (5 ml) was stirred at room temperature for 6hours. The reaction was quenched with trifluoroacetic acid (2 ml) andconcentrated. The residue was purified on a reverse phase HPLC usingacetonitrile/water (0.5% TFA) gradient to give the desired product as aviscous oil (80 mg). The ¹H NMR was consistent with the proposedstructure. Elemental analysis: calculated for C₁₉H₂₀N₂F₂O₃.TFA: C,52.95;H, 4.44; N, 5.88; Found: C, 52.39;H, 4.60; N, 5.62.

EXAMPLE 5(2-{4-[2-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-phenyl}-cyclopropyl)-aceticAcid

[0332]

[0333] Step 1

[0334] 2-(3-methyl-2-pyridinyl)1H-isoindole-1,3 (2H)-dione

[0335] To a neat 2-amino-3-picoline (91 g, 0.84 mol) was addedphthalicanhydrous (125 g, 0.84 mol), the resulting solid mixture washeated at 120° C. and water was distilled off from the reaction mixture.The reaction mixture was cooled to room temperature and solid wasdissolved in methylenechloride (1 L). The organic solution was washedwith water (2×500 ml), brine (1×500 ml), dried over MgSO₄. The colorsolution was treated with activated carbon, filtered and filtrate wasconcentrated under reduced pressure. Ether (300 ml) was added to theconcentrated residue and stirred at room temperature overnight. Solidwas filtered and washed with ether, dried to give 176 g (88%) whitesolid. NMR (DMSO) δ 2.17 (m, 3H), 7.46-7.49 (m, 1H), 7.88-8.01 (m, 5H),8.44-8.46 (m, 1H). Mass spectrometry: 239.19 (M+H)⁺.

[0336] Step 2

[0337] 2-[3-(dibromomethyl)-2-pyridinyl]-1H-isoindole-1,3(2H)-dione

[0338] To a suspension solution of2-(3-methyl-2-pyridinyl)1H-isoindole-1,3 (2H)-dione (14.6 g, 61 mmol)and NBS (25 g, 140 mmol) in CCl₄ (160 mL) was added AIBN (0.1 g), thereaction mixture was refluxed and a irradiated with a sun lamp. AIBN(0.1 g) were added every 30 minutes until the starting material was allconsumed. The mixture was cooled to room temperature and solid wasfiltered. Solid was taken up to methylenechlorid (400 ml) and washedwith 5% Na₂S₂O₃ (3×150 ml), water (1×150 ml) and dried over Na₂SO₄. Thesolvent was removed under reduced pressure. The concentrated solid wassuspended in ether. Solid was filtered and dried to give 20.5 g (84.5%)yellow solid. NMR (DMSO) δ 7.6 (s, 1H), 7.74-7.78(m, 1H), 7.92-8.01 (m,4H), 8.51-8.55 (m, 1H), 8.63-8.64 (m, 1H). Mass spectrometry: 396.92(M+H)⁺.

[0339] Step 3

[0340] 2-amino-3-pyridinecarboxaldehyde

[0341] The compound was prepared according to the procedure as describedby A. E. Moormann et al, Synthetic Communications, 17(14), 1695-1699(1987) To a solution of2-[3-(dibromomethyl)-2-pyridinyl]-1H-isoindole-1,3(2H)-dione (20 g, 50mmol) in ethanol (250 ml) was added conc. NH₄OH (25 ml) at 4° C. Thereaction mixture was stirred 10 minutes at 4° C. then stirred at roomtemperature for one hour. Reaction mixture was concentrated underreduced pressure. To the concentrated residue was added con. HCl (150ml) and mixture was refluxed for 3 hours. The reaction mixture wascooled to room temperature and concentrated. To the concentrated residuewas added water (25 ml) then added saturated K₂CO₃ to neutralize thesolution. The solution was extracted with methylenechloride (3×150 ml).Combined organic solution was washed with water (3×150 ml), brine (1×200ml), dried over Na₂SO₄, concentrated. The concentrated residue wassuspended in ether, filtered and washed with ether to give 4.3 g (70%)yellow solid. NMR (DMSO) δ 6.69-6.73 (m, 1H), 7.51 (bs, 2H),7.95-7.98(m, 1H), 8.20-8.22 (m, 1H), 9.82 (s, 1H).

[0342] Step 4

[0343] 2-methyl-1,8-naphthyridine

[0344] The compound was prepared according to the procedure as describedby E. M. Hawes and D. G. Wibberley, J. Chem. Soc. (C), 1966, 315. To asolution of 2-amino-3-pyridinecarboxaldehyde (2 g, 16 mmol) in ethanol 3ml) was added acetone (1.9 g, 32 mmol) and peperidine (0,34 g, 4 mmol)and the reaction mixture was refluxed 24 hours. Reaction mixture wascooled to room temperature then concentrated in vacuum. Ether was addedto concentrated residue. Solid was filtered and dried to give 1.62 g(69%) yellow solid. NMR (CD₃OD) δ 2.76 (s, 3H), 7.52-7.58 (m, 2H), 8.30(d, 2H, J=8.33 Hz), 8.36-8.39 (m, 1H), 8.39-8.99 (m, 1H).

[0345] Step 5

[0346] 2-methyl-5,6,7,8-tetrahydro-1,8-naphthyridine

[0347] The compound was prepared according to the procedure as describedin WO 0033838. To a solution of 2-methyl-1,8-naphthyridine (2 g, 13.9mmol) in ethanol (35 ml) was added 10% Pd/C, and the reaction mixturewas stirred under H₂ (10 psi) for 24 hours. Palladium was filtered outthrough celite and washed with excess ethanol. The filtrate wasconcentrated under vacuum to give 1.7 g (83%) pink solid. NMR (CD₃OD) δ1.82-1.87 (m, 2H), 2.22 (s, 3H), 2.65-2.76 (m, 2H), 3.33-3.36 (m, 2H),6.32 (d, 1H, J=7.25 Hz), 7.07 (d, 1H, J=7.38 Hz). Mass spectrometry:149.15 (M+H)⁺.

[0348] Step 6

[0349]2-methyl-8-(tert-butoxycarbonyl)-5,6,7,8-tetrahydro-1,8-naphthyridineThe compound was prepared according to the procedure as described in WO0033838. To a solution of 2-methyl-5,6,7,8-tetrahydro-1,8-naphthyridine(1 g, 6.7 mmol) in methylenechloride (10 ml) was added di-tert-butyldicarbonate (3 g, 13 mmol), triethylamine (0.68 g, 6.7 mmol) and 4-DMAP(50 mg), the reaction mixture was refluxed overnight. The reactionmixture was concentrated under vacuum. The concentrated residue waspurified on silica gel (1% methanol in methylenechloride) to give 1.1 g(69%) orange solid. NMR (CD₃OD) δ 1.50 (s, 9H),1.88-1.95 (m, 2H), 2.43(s, 3H), 2.73-2.78 (m, 2H), 3.29-3.31 (m, 2H), 3.72-3.76 (m, 2H), 6.95(d, 1H, J=7.76 Hz), 7.44 (d, 1H, J=7.76 Hz).

[0350] Step 7

[0351] Ethyl[8-(tert-butoxycarbonyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl]acetate

[0352] The compound was prepared according to the procedure as describedin WO 0033838. To a solution of2-methyl-8-(tert-butoxycarbonyl)-5,6,7,8-tetrahydro-1,8-naphthyridine(1.4 g, 5.6 mmol) and diethylcarbonate (2.5 g, 20 mmol) in THF (10 ml)was added LDA (8 ml of 2M solution in hexane) at −78° C. and stirred at−78° C. for 40 minutes. The reaction was quenched with saturated NH₄Cland extracted with ethylacetate (2×100 ml). Combined organic solutionwas concentrated and purified on silica gel column to give 1.5 g (83%)yellow oil. NMR (CD₃OD) δ 1.25 (t, 3H, J=7.10 Hz), 1.51 (s, 9H),1.88-1.97 (m, 2H), 2.75 (t, 2H, J=6.59 Hz), 3.74-3.80 (m, 4H), 4.10-4.20(m, 2H), 7.0 (d, 1H, J=7.61 Hz), 7.39 (d, 1H, J=7.47 Hz).

[0353] Step 8

[0354] 2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)-1-ethanol

[0355] The compound was prepared according to the procedure as describedin WO 0033838. To a solution of ethyl[8-(tert-butoxycarbonyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl]acetate(3.8 g, 11.8 mmol) in THF (20 ml) was added LiBH₄ (7.6 ml of 2M solutionin hexane, 15.2 mmol), the reaction was refluxed overnight. The reactionmixture was cooled in ice bath and quenched with water. The mixture wasextracted with ethylacetate (3×50 ml). The combined organic solution wasdried over MgSO₄, concentrated and dried under vacuum to give 2.9 g oil.The oil was taken up in methylenechloride (10 ml) and 4N HCl in dioxane(10 ml) was added. The solution was stirred 4 hours at room temperaturethen concentrated under vacuum. To the concentrated residue was added1:1/1N NaOH:brine (50 ml) and extracted with methylenechloride (3×80ml). The combine organic solution was concentrated and purified onsilica gel to give 1 g (47%) oil. NMR (CD₃OD) δ 1.82-1.88 (m, 2H),2.66-2.71 (m, 4H), 3.45 (t, 2H, J=5.57 Hz), 3.77 (t, 2H, J=6.84 Hz),6.36 (d, 1H, J=7.38 Hz), 7.10 (d, 1H, J=7.38 Hz).

[0356] Step 9

[0357] To a solution of2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)-1-ethanol (WO 00/33838;0.18 g, 1 mmole) and PPh3 (0.26 g, 1 mmole) in dry THF (4 mL) was addedcyclopropyl phenol (0.1 g, 0.45 mmole) in dry THF (3 mL) and diisopropylazodicarboxylate (0.17 g, 1 mmole). The reaction mixture was stirred atroom temperature. After 18 hours, the mixture was concentrated underreduced pressure and purified on reverse phase HPLC. The ethyl ester oftitle compound (0.1 g, 45%) was dissolved in 3 mL 50% acetonitrile inwater and LiOH (40 mg) was added. The reaction mixture was heated at 50°C. for one hour then acidified by adding TFA. The residue was purifiedon reverse phase HPLC to give the title compound (50 mg, 53%) as TFAsalt: HRMS: (MH+)=353.1876. NMR (400 MHz, CD₃OD) δ 0.76-0.84(??m, 1H),0.85-0.88 (m, 1H), 1.20-1.24 (m, 1H), 1.68-1.71 (m, 1H), 1.90-1.96 (m,2H), 2.28-2.40 (m, 2H), 2.80 (t, 2H, J=6.24 Hz), 3.10 (t, 2H, J=5.98Hz), 3.48 (t, 2H, J=5.71 Hz), 4.22 (t, 2H, J=5.97 Hz), 6.70 (d, 1H,J=7.38 Hz), 6.76-6.79 (m, 2H), 6.98-7.01 (m, 2H), 7.57 (d, 1H, J=7.38Hz).

EXAMPLE 62-[3-methyl-4-[3-(2-pyridinylamino)propoxy]phenyl]cyclopropaneaceticAcid

[0358]

[0359] Step 1

[0360] 4-hydroxy-3-methylbenzaldehyde (3.0 g, 22 mmol) was dissolved inDMF (25 ml). Imidazole (2.72 g, 40 ml) and dimethyl-t-butylsilylchloride (3.76 g, 25 mmol) were added. After 30 min, the product wasextracted with ethyl acetate, and washed with H₂O. The aqueous layer wasextracted with additional ethyl acetate. The combined organic layer waswashed with H₂O, brine, and dried. The crude product was purified byvacuum distillation to afford a clean oil in 4.1 g. NMR spectra of theproduct were consistent for the proposed structure.

[0361] Step 2

[0362] Under N₂, a solution of triethyl phosphonoacetate (4.5 g, 20mmol) in 40 ml THF was added to a suspension of sodium hydride (0.8 g,20 mmol, 60% dispersion in mineral oil) in 40 ml THF at 0° C. Theresulting mixture was stirred at 0° C. for 30 min. A solution of theproduct of step 1 (4.1 g, 16.4 mmol) in 20 ml THF was added. Thereaction was allowed to warm to room temperature and then was stirred atreflux for 1 h. The cooled reaction was quenched with 1N HCl solution.The product was extracted with ethyl acetate. The aqueous layer wasextracted with additional ethyl acetate. The combined ethyl acetatelayer was washed with H₂O and brine, dried with Na₂SO₄, andconcentrated. The residue was purified by chromatography (on silica gel,EA/hexane5/95) to give a colorless liquid in 4.5 g. NMR spectra of theproduct were consistent for the proposed structure.

[0363] Step 3

[0364] A solution of n-BuLi (12.4 ml, 30.9 mmol, 2.5M in hexane) wasadded to a solution of 2,2,6,6-tetramethylpiperidine (4.8 g, 33.7 mmol)in 35 ml THF at 0° C. to form LTMP. In a separate flask, a solution ofthe product of step 2 (4.5 g, 14.04 mmol) and dibromomethane (5.3 g,30.9 mmol) in 30 ml of THF was cooled to −70° C. After 30 min, LTMPsolution was cooled to −70° C., and added to above solution via acannula over 30 min at −65° C. After 10 min, a solution of lithiumbis(trimethyl)silyl amide solution (28 ml, 28 mmol, 1M in THF) was addedover 15 min at −70° C. The resulting mixture was allowed to warm to −20°C. and then cooled back to −70° C. A solution of s-BuLi solution (43.2ml, 56.2 mmol, 1.3 M in cyclohexane) was added at −60° C. over 15 min.The mixture was allowed to warm to room temperature. A solution ofn-BuLi (12.4 ml, 28 mmol, 2.5 in hexane) was added to the reaction, andthe reaction was stirred at room temperature for 1 h. The reaction wascooled to −70° C. and transferred into an acidic ethanol solution (15 mlacetyl chloride and 75 ml ethanol) at 0° C. via a cannula over 1 h. Theresulting mixture was diluted with 280 ml ether and washed with 280 ml10% HCl solution. The aqueous layer was extracted with ether. Thecombined organic layer was washed with brine, dried with MgSO₄, andconcentrated. The residue was purified by chromatography (on silica gel,ethyl acetate/hexane=5/95) to give a brown liquid in 1.65 g. NMR spectraof the product were consistent for the proposed structure.

[0365] Step 4

[0366] Under N₂, a solution of diethyl zinc (5.5 ml, 5.5 mmol, 1.0 M inhexane) was added to a solution of diiodomethane (2.95 g, 11.0 mmol) in15 ml dichloromethane at 0° C. After 15 min, a solution of the productof step 3 (1.65 g, 4.9 mmol) in 5 ml dichloromethane was added at 0° C.dropwise. The reaction was warmed to 35° C. After 30 min, the reactionwas cooled to 0° C. and quenched with H₂O. The product was extractedwith ethyl acetate and washed with 1N HCl. The aqueous layer wasextracted with ethyl acetate. The combine organic layer was washed withH₂O, brine, dried with Na_(0.2)SO₄, and concentrated to give a brown oilin 1.22 g. This product was used without further purification. NMRspectra of the product were consistent for the proposed structure.

[0367] Step 5

[0368] Potassium fluoride (0.3 g, 5.1 mmol) was added to a solution ofthe product of step 4 (1.22 g, 3.5 mmol) in 15 ml DMF and 1.0 ml H₂O.The reaction was stirred at room temperature for 18 h. The product wasextracted with ethyl acetate. The aqueous layer was extracted with anadditional ethyl acetate. The combined organic layer was washed withH₂O, brine, dried with Na₂SO₄, and concentrated. The residue waspurified by chromatography (on silica gel, EA/hexane=3/7) to yield apale brown oil in 0.373 g. This product was used without furtherpurification. NMR spectra of the product were consistent for theproposed structure.

[0369] Step 6

[0370] A solution of diethyl azodicarboxylate (0.348 g, 2.0 mmol) in 3ml THF was added to a solution of the product of step 5 (0.37 g, 1.6mmol) and triphenylphosphine (0.525 g, 2.0 mmol) in 12 ml THF at roomtemperature. After 15 min, 2-(3-Hydroxypropylamino)pyridine N-oxide(0.336 g, 2 mmol) was added. The reaction was stirred at roomtemperature for 18 h and concentrated. The residue was purified bychromatography (on silica gel, C₂HCl₂/CH₃OH/NH₄OH=98.5/1/0.5) to yield apale brown oil in 0.127 g. NMR spectra of the product were consistentfor the proposed structure.

[0371] Step 7

[0372] A solution of the product of step 6 (0.25 g, 0.65 mmol), ammoniumformate (0.41 g, 6.5 mmol), and 10% palladium on carbon (0.075 g, 0.07mmol) in 5 ml methanol was stirred at room temperature for 20 h.Additional ammonium formate (0.41 g, 6.5 mmol) and 10% Palladium oncarbon (0.075 g, 0.07 mmol) were added. After 20 h, the reaction wasfiltered through a short column of Celite® and washed with ethanol. Thefiltrate was concentrated and residue was purified by chromatography (onsilica gel, C₂HCl₂/CH₃OH/NH₄OH=98.5/1/0.5) to afford a pale brown oil in0.127 g). NMR spectra of the product were consistent for the proposedstructure.

[0373] Step 8

[0374] A solution of the product of step 7 (0.095 g, 0.26 mmol) in 5 ml1 N NaOH and 5 ml methanol was stirred at room temperature for 18 h. Thereaction was acidified with 1.5 ml trifluoroacetic acid andconcentrated. The residue was purified on HPLC using acetonitrilegradient 10-50% in 30 min to yield 40.3 mg. FAB-MS:(MH+)=341.4. ¹H NMR(CDCl₃) δ 0.81 (dt, 1H), 0.99 (dt, 1H), 1.31 (m, 1H), 1.71 (dt, 1lH),2.19 (s, 3H), 2.19 (p, 2H), 2.43 (d, 2H), 3.54 (q, 2H), 4.03 (t, 2H),6.71 (m, 2H), 6.83 (d, 1H), 6.89 (m, 2H), 7.76 (t, 1H), 7.80 (d, 1H),9.61 (br, 1H). Anal Calcd. for C₂₀H₂₄N₂O₃ plus 1.25 CF₃COOH: C, 55.96;H,5.27; N, 5.80. Found: C, 56.05;H, 5.47; N, 5.78.

EXAMPLE 72-[2-methoxy-4-[3-(2-pyridinylamino)propoxy]phenyl]cyclopropaneaceticAcid

[0375]

[0376] The title compound was prepared according to the generalprocedures described for the preparation of EXAMPLE 6:H NMR(CDCl3) δ0.78 (dt, 1H), 0.96 (dt, 1H), 1.19 (m, 1H), 1.86 (dt, 1lH), 2.19 (p,2H), 2.38 (dd, 1H), 2.56 (dd, 1H), 3.51 (t, 2H), 3.83 (s, 3H), 4.06 (t,2H), 6.39 (dd, 1H), 6.44 (d, 1H), 6.69 (t, 1H), 6.81 (d, 1H), 6.85 (d,1H), 7.75 (t, 1H), 7.77 (d, 1H). Anal Calcd. for C₂₀H₂₄N₂O₄ plus 0.9CF₃COOH: C, 57.04;H, 5.47; N, 6.10. Found: C, 57.08;H, 5.38; N, 6.21.

EXAMPLE 82-[2-methyl-4-[3-(2-pyridinylamino)propoxy]phenyl]cyclopropaneaceticAcid

[0377]

[0378] Step 1

[0379] 3,4-Dimethyl anisole (6.0 g, 44.0 mmol) was dissolved in 200 mlmethanol. A solution of ammonium cerium (IV) nitrate in 300 ml methanolwas added at room temperature over 5 min and the reaction was stirredfor 10 min. The reaction was diluted with 300 ml H₂O. The product wasextracted with dichloromethane. The organic layer was washed with brine,dried with Na₂SO₄, and concentrated. The residue was purified bychromatography (on silica gel, ethyl acetate/hexane=1/9) to afford agreenish liquid in 5.7 g. NMR spectra of the product were consistent forthe proposed structure.

[0380] Step 2

[0381] A solution of triethyl phosphonoacetate (11.2 g, 50 mmol) in 50ml THF was added to a mixture of sodium hydride (1.2 g, 50 mmol) in 50ml THF at 0° C. After 30 min, a solution of the product of step 1 (5.7g, 40 mmol) in 25 ml THF was added at 0° C. The reaction was heated atreflux for 1 h. The reaction was diluted with ethyl acetate, and 1N HClsolution. The aqueous layer was extracted with additional ethyl acetate.The combined organic layer was washed with H₂O, brine, dried withNa₂SO₄, and concentrated. The residue was purified by chromatography (onsilica gel, ethyl acetate/hexane=15/85) to give a colorless liquid in7.89 g. NMR spectra of the product were consistent for the proposedstructure.

[0382] Step 3

[0383] A solution of n-butyllithium (17.6 ml, 44 mmol, 2.5M in hexane)was added to a solution of 2,2,6,6-tetramethylpiperidine (6.8 g, 48mmol) in 50 ml THF at 0° C. to form LTMP. In a separate flask, asolution of the product of step 2 (4.4 g, 20 mmol) and dibromomethane(7.6 g, 44 mmol) in 40 ml THF was cooled to −70° C. After 30 min, LTMPsolution was cooled to −70° C., and added to above solution via acannula at −65° C. over 30 min. After 10 min, a solution of lithiumbis(trimethyl)silyl amide solution (40 ml, 40 mmol, 1M in THF) was addedover 15 min at −70° C. The resulting mixture was allowed to warm to −20°C. and then cooled back to −70° C. A solution of s-butyllithium solution(61.6 ml, 80 mmol, 1.3 M in cyclohexane) was added at −60° C. over 15min. The mixture was warmed to room temperature. A solution of n-BuLi(17.6 ml, 40 mmol, 2.5 in hexane) was added, and the reaction wasstirred at room temperature for 1 h. It was cooled to −70° C. andtransferred into an acidic ethanol solution (20 ml acetyl chloride and100 ml ethanol) at 0° C. via a cannula over 1 h period. The resultingmixture was diluted with 400 ml ether and washed with 400 ml 10% HClsolution. The aqueous layer was extracted with ether. The combinedorganic layer was washed with brine, dried with MgSO₄, and concentrated.The residue was purified by chromatography (on silica gel, ethylacetate/hexane=1/9) to give a brown liquid in 1.17 g. NMR spectra of theproduct were consistent for the proposed structure.

[0384] Step 4

[0385] Under N₂, diethyl zinc solution (5.5 ml, 5.5 mmol, 1.0 M inhexane) was added to a solution of diiodomethane (2.95 g, 11 mmol) in 15ml dichloromethane at 0° C. After 15 min, a solution of the product ofstep 3 (1.15 g, 4.9 mmol) in 5 ml dichloromethane was added dropwise at0° C. The reaction was heated at 35° C. for 30 min. The reaction wasquenched with H₂O at 0° C. and acidified with 1N HCl. The product wasextracted with ethyl acetate. The aqueous layer was extracted withadditional ethyl acetate. The combined organic layer was washed withH₂O, brine, dried with Na₂SO₄, and concentrated to afford a brown oil in1.42 g. This product was used without further purification. NMR spectraof the product were consistent for the proposed structure.

[0386] Step 5

[0387] The product of step 4 (1.42 g, 5.7 mmol) was dissolved in 15 mldichloromethane. Under N₂ boron tribromide solution (11 ml, 11 mmol, 1Min dichloromethane) was added to the above solution dropwise at 0° C.The reaction was allowed to warm to room temperature. After 30 min, thereaction was carefully quenched with ethanol. The product was extractedwith ethyl acetate and washed with 1N HCl. The organic layer was furtherwashed with 5% NaHCO₃ solution, brine, dried with MgSO₄, andconcentrated. The residue was purified by chromatography (on silica gel,ethyl acetate/hexane=2/8) to give a pale brown oil in 0.175 g. NMRspectra of the product were consistent for the proposed structure.

[0388] Step 6 A solution of diethyl azodicarboxylate (174 mg, 1.0 mmol)in 1 ml THF was added to a solution of the product of step 5 (175 mg,0.75 mmol) and triphenylphosphine (262 mg, 1 mmol) in 5 ml THF at roomtemperature and stirred for 15 min. 2-(3-Hydroxypropylamino)pyridineN-oxide (168 mg, 1 mmol) was added. The reaction was stirred at roomtemperature for 18 h and concentrated. The residue was purified bychromatography (on silica gel, CH₂Cl₂/CH₃OH/NH₄OH-98.5/1/0.5) to afford127 mg pale brown oil. NMR spectra of the product were consistent forthe proposed structure.

[0389] Step 7

[0390] A mixture of the product of step 6 (127 mg, 0.3 mmol), 10% Pd/C(50 mg, 0.04 mmol), cyclohexene (2.0 ml, 17.8 mmol), and 2-propanol (5.0ml) was heated at reflux for 4 h. The reaction was allowed to cool toroom temperature. Additional 10% Pd/C (50 mg, 0.04 mmol) was added.After 18 h of refluxing, the reaction was cooled to room temperature,filtered through a short column of Celite®, and washed with 100 ml of2-propanol. The filtrate was concentrated to give 85 mg oil. Thisproduct was used without further purification. The NMR spectra wereconsistent for the proposed structure.

[0391] Step 8

[0392] The product of step 7 (70 mg, 0.19 mmol) was dissolved in 5 mlmethanol and 5 ml 1 N sodium hydroxide solution. The reaction wasstirred at room temperature for 5.5 h, acidified with 2 mltrifluoroacetic acid, and concentrated. The residue was purified on HPLCusing acetonitrile gradient 10-50% in 30 min to yield 82.7 mg of gummysolid. FAB-MS:(MH+)=341.H NMR(CDCl₃) δ 0.82 (m, 1H), 0.89 (m, 1H), 1.31(m, 1H), 1.70 (dt, 1H), 2.19 (p, 2H), 2.35 (s, 3H), 2.50 (m, 2H), 3.53(m, 2H), 4.04 (t, 2H), 6.64 (dd, 1H), 6.71 (m, 2H), 6.85 (t, 1H), 6.96(d, 1H), 7.78 (m, 2H). Anal Calcd. for C₂₀H₂₄N₂O₃ plus 1.25 CF₃COOH: C,55.96;H, 5.27; N, 5.80. Found: C, 56.24;H, 5.36; N, 5.95.

EXAMPLE 92-[3-fluoro-4-[3-(2-pyridinylamino)propoxy]phenyl]cyclopropaneaceticAcid

[0393]

[0394] Step 1

[0395] A solution of triethyl phosphonoacetate (16.8 g, 75 mmol) in 50ml THF was added to a mixture of sodium hydride (1.8 g, 75 mmol) in 125ml THF at 0° C. After 30 min, 3-fluoro-p-anisaldehyde (10.0 g, 64.9mmol) in 25 ml THF was added at 0° C., and the reaction was stirred atroom temperature for 30 min. The reaction was diluted with ethylacetate, washed with 1N HCl solution. The aqueous layer was extractedwith additional ethyl acetate. The combined organic layer was washedwith H₂O, brine, dried with Na₂SO₄, and concentrated. The residue waspurified by chromatography (on silica gel, ethyl acetate/hexane=1/4) togive a colorless liquid in 12.9 g. NMR spectra of the product wereconsistent for the proposed structure.

[0396] Step 2 The product of step 1 (8.4 g, 37.5 mmol) was dissolved in75 ml THF. Under N₂ a solution of diisobutylalumium hydride (150 ml, 1 Min THF) was added at 0° C. over 30 min. The reaction was stirred for 30min and quenched with 250 ml 1N HCl solution. The mixture was stirredfor 15 min and filtered through a short column of Celite®. The productwas extracted with ethyl acetate. The aqueous layer was extracted withethyl acetate. The combined organic layer was dried with MgSO₄ andconcentrated. The residue was purified by chromatography (on silica gel,ethyl acetate/hexane=2/3) to give a white solid in 3.32 g. NMR spectraof the product were consistent for the proposed structure

[0397] Step 3

[0398] Under N₂, diethyl zinc solution (75 ml, 75 mmol, 1.0 M in hexane)was added dropwise to a solution of diiodomethane (40.2 g, 150 mmol) in200 ml methylene chloride at 0° C. After stirring at 0° C. for 15 min, asolution of the product of step 2 (10.6 g, 58.2 mmol) in 50 ml methylenechloride was added at 0° C. dropwise. The reaction was warmed to 35° C.After 30 min, the reaction was quenched with H₂O at 0° C. and acidifiedwith 1N HCl. The product was extracted with ethyl acetate. The aqueouslayer was extracted with additional ethyl acetate. The combined organiclayer was washed with H₂O, brine, dried with Na₂SO₄, and concentrated.The residue was purified by chromatography (on silica gel, ethylacetate/hexane=2/3) to afford a pale brown oil in 9.6 g. NMR spectra ofthe product were consistent for the proposed structure.

[0399] Step 4

[0400] Under N₂ DMSO (8.6 g, 110 mmol) in 30 ml methylene cloride wasadded to a solution of oxalyl chloride (7.0 g, 55.0 mmol) in 30 mlmethylene chloride dropwise at −60° C. and stirred for 2 min. A solutionof the product of step 3 (9.6 g, 48.9 mmol) in 40 ml methylene cloridewas added at −60° C. and the reaction was stirred for 15 min. Triethylamine (22.8 g, 225 mmol) was added at −60° C. The reaction was stirredfor 15 min and allowed to warm to room temperature. The reaction wasquenched with 50 ml H₂O and the product was extracted with methylenechloride. The organic layer was washed with 1% HCl, 5% Na₂CO₃, brine,dried with Na_(0.2)SO₄, and concentrated. The residue was purified bychromatography (on silica gel, ethyl acetate/hexane=3/7) to afford awhite solid in 7.32 g. NMR spectra of the product were consistent forthe proposed structure.

[0401] Step 5

[0402] Under N₂ atmosphere, lithium bis(trimethylsilyl) amide solution(50 ml, 1.0M in THF) was added to a mixture of methoxy methyltriphenylphosphonium chloride (17.1 g, 37.6 mmol) in 90 ml THF dropwise at 0° C.After 15 min, it was added to a solution of the product of step 4 (7.3g, 37.6 mmol) in 60 ml THF at 0° C. The reaction was stirred for 5 minand quenched with H₂O. The product was extracted with ethyl acetate. Theaqueous layer was extracted with ethyl acetate. The combined organiclayer was washed with H₂O, brine, and then dried with Na_(0.2)SO₄ andconcentrated. The residue was purified by chromatography (on silica gel,ethyl acetate/hexane=1/9) to yield a colorless oil in 5.32 g. It wasdissolved in 150 ml THF and 100 ml 2N HCl solution. The reaction wasstirred at reflux for 15 min. THF was evaporated and the residue wasdiluted with H₂O and ethyl acetate. The aqueous layer was extracted withethyl acetate. The combined organic layer was washed with 5% NaHCO₃solution, brine, and dried with MgSO₄, and concentrated. The residue waspurified by chromatography (on silica gel, ethyl acetate/hexane=1/9) toyield a colorless oil in 4.52 g. NMR spectra of the product wereconsistent for the proposed structure.

[0403] Step 6

[0404] A solution of silver nitrate (3.26 g, 19.3 mmol) in 6 ml H₂O wasadded to a solution of the product of step 5 (2.0 g, 9.6 mmol) in 45 mlethanol. A solution of Sodium hydroxide (1.54 g, 38.4 mmol) in 6 ml H₂Owas added dropwise at room temperature. After 2 h, the reaction wasfiltered through a pad of Celite®. The residue was diluted with H₂O andextracted with ether (3×30 ml). The aqueous layer was acidified withconcentrated HCl and extracted with chloroform. The organic layer wasdried with MgSO₄ and concentrated to give 1.82 g of yellow solid. Thissolid was dissolved in 50 ml ethanol and 25 ml 4N HCl in dioxane. It wasstirred at room temperature for 48 h. Ethanol and dioxane wereevaporated to afford a clean product as a pale brown oil in 2.0 g. NMRspectra of the product were consistent for the proposed structure.

[0405] Step 7

[0406] The product of step 6 (2.0 g, 8.6 mmol) was dissolved in 15 mlmethylene chloride. Under N₂boron tribromide solution (15 ml, 15 mmol,1M in methylene chloride) was added to the above solution dropwise at 0°C. The resulting reaction solution was allowed to warm to roomtemperature. After 30 min, the reaction was carefully quenched withethanol. The product was extracted with ethyl acetate and washed with 1NHCl. The organic layer was washed with 5% NaHCO₃ solution, brine, driedwith MgSO₄, and concentrated. The residue was purified by chromatography(on silica gel, ethyl acetate/hexane=3/7) to give pale brown oil in 1.63g. NMR spectra of the product were consistent for the proposedstructure.

[0407] Step 8

[0408] A solution of diethyl azodicarboxylate (731 mg, 4.2 mmol) in 5 mlTHF was added to a solution of the product of step 7 (750 mg, 3.4 mmol)and triphenylphosphine (1.1 g, 4.2 mmol) in 20 ml THF at roomtemperature and stirred for 15 min. 2-(3-hydroxypropylamino)pyridineN-oxide (706 mg, 4.2 mmol) was added. The reaction was stirred at roomtemperature for 18 h. THF was evaporated and the residue was purified bychromatography (on silica gel, CH₂Cl₂/CH₃OH/NH₄OH-98.5/1/0.5) to yield835 mg pale brown oil. NMR spectra of the product were consistent forthe proposed structure.

[0409] Step 9

[0410] A mixture of the product of step 8 (835 mg, 2.15 mmol), 10% Pd/C(250 mg, 0.24 mmol), cyclohexene (3.0 ml, 29.6 mmol), and 2-propanol (20ml) was heated at reflux for 4 h. The reaction was allowed to cool toroom temperature. Additional 10% Pd/C (250 mg, 0.24 mmol) was added.After 4 h of refluxing, the reaction was cooled to room temperature,filtered through a short column of Celite®, and washed with 2-propanol.The filtrate was concentrated. The residue was purified bychromatography (on silica gel, CH₂Cl₂/CH₃OH/NH₄OH=98.5/1/0.5) to give482 mg colorless oil. The NMR spectra were consistent for the proposedstructure.

[0411] Step 10

[0412] The product of step 9 (475 mg, 1.28 mmol) was dissolved in 10 mlmethanol and 10 ml 1N sodium hydroxide solution. The reaction wasstirred at room temperature for 18 h and acidified with 2 mltrifluoroacetic acid. Solvents were evaporated. The residue was purifiedon HPLC using acetonitrile gradient 10-50% in 30 min to yield 434 mggummy solid. FAB-MS:(MH+)=345.4.H-NMR(CDCl₃) δ 0.86 (dt, 1H), 0.95 (dt,1H), 1.30 (m, 1H), 1.72 (dt, 1lH), 2.18 (p, 2H), 2.40 (dd, 1H), 2.49(dd, 1H), 3.58 (t, 1H), 4.10 (t, 2H), 6.72 (t, 1H), 6.80-6.90 (m, 3H),6.95 (d, 1H), 7.80 (t, 1H), 7.81 (d, 1H), 9.09 (br, 1H). Anal Calcd. forC₁₉H₂₁N₂O₃F plus 1.5 CF₃COOH: C, 51.27;H, 4.40; N, 5.44. Found: C,51.12;H, 4.40; N, 5.57.

EXAMPLE 102-[2-fluoro-4-[3-(2-pyridinylamino)propoxy]phenyl]cyclopropaneaceticAcid

[0413]

[0414] The title compound was prepared according to procedure describedfor the preparation of EXAMPLE 12: FAB-MS:(MH+)=345.4. ¹H NMR (DMSO-6d)δ 0.82 (dt, 1H), 0.86 (dt, 1H), 1.23 (m, 1H), 1.78 (dt, 1H), 2.04 (p,2H), 2.31 (dd, 1H), 2.37 (dd, 1H), 3.48 (t, 2H), 4.07 (t, 2H), 6.69 (dd,1H), 6.77 (dd, 1H), 6.86 (t, 1H), 6.96 (t, 1H), 7.06 (d, 1H), 7.90 (t,1H), 7.94 (d, 1H), 8.84 (br, 1H). Anal Calcd. for C₁₉H₂₁N₂O₃F plus 1.75CF₃COOH: C, 49.68;H, 4.22; N, 5.15. Found: C, 49.58;H, 3.96; N, 5.09.

EXAMPLE 112-[4-[2-[6-(methylamino)-2-pyridinyl]ethoxy]phenyl]cyclopropaneaceticAcid

[0415]

[0416] Step 1

[0417] A mixture of trans-4-methoxycinnamic acid (50 g, 281 mmol), 5 mlconcentrated H₂SO₄, and 500 ml ethanol was stirred at reflux for 18 h.The cooled reaction was quenched with saturated NaHCO₃ solution. Theproduct was extracted with ether. The organic layer was dried with MgSO₄and concentrated. The residue was solidified at room temperature toyield a pale brown solid in 54.8 g. NMR spectra of the product wereconsistent for the proposed structure.

[0418] Step 2

[0419] The product of step 1 (20.6 g, 100 mmol) was dissolved in 150 mlTHF. It was added to a solution of diisobutylalumium hydride (300 ml, 1Min THF) diluted with THF (150 ml) at 0° C. under N₂ over 20 min. After 1h, the reaction was quenched with 50 ml acetone and 25 ml ethanol. Theresulting mixture was poured into H₂O and acidified with 1N HCl. Theproduct was extracted with ethyl acetate. The organic layer was driedwith MgSO₄, and concentrated to yield an off-white solid in 15.62 g.This product was used without further purification. NMR spectra of theproduct were consistent for the proposed structure.

[0420] Step 3

[0421] Diethyl zinc solution (100 ml, 100 mmol, 1.0 M in hexane) wasadded to a solution of diiodomethane (16.1 ml, 200 mmol) in 175 mldichloromethane at 0° C. over 15 min. After stirring at 0° C. for 15min, a solution of the product of step 2 (15.6 g, 95 mmol) in 50 mldichloromethane was added dropwise at 0° C. over 15 min. After 15 min,the reaction was quenched with 200 ml 1N HCl at 5° C. The product wasextracted with dichloromethane. The organic layer was dried with MgSO₄and concentrated to give a golden oil in 16.47 g. NMR spectra of theproduct were consistent for the proposed structure.

[0422] Step 4

[0423] The product of step 3 (3.5 g, 19.6 mmol) was dissolved in 40 mldichloromethane. 4-methylmorpholine-N-oxide (3.5 g, 30 mmol) and drymolecular sieves (10.0 g, 4A) were added. The resulting mixture wasstirred at room temperature for 15 min. Tetrapropylammonuim perruthenate(0.351 g, 1.0 mmol) was added. The reaction was stirred at roomtemperature for 2.5 h and filtered through a short column of Celite®.The filtrate was concentrated and residue was purified by chromatography(on silica gel, ethyl acetate/hexane=3/7) to afford a golden oil in 1.9g. NMR spectra of the product were consistent for the proposedstructure.

[0424] Step 5

[0425] Under N₂, lithium bis(trimethylsilyl) amide solution (90 ml, 1.0Min THF) was added to a mixture of methoxy methyltriphenyl phosphoniumchloride (29.2 g, 85 mmol) in 60 ml THF dropwise at 0° C. After 15 min,it was added to a solution of the product of step 4 (10.0 g, 56.8 mmol)in 30 ml THF was added at 0° C. The reaction was stirred for 5 min andquenched with H₂O. The product was extracted with ethyl acetate. Theaqueous layer was extracted with ethyl acetate. The combined organiclayer was washed with H₂O, brine, dried with Na₂SO₄, and concentrated.The residue was purified by chromatography (on silica gel, ethylacetate/hexane=1/9) to yield a pale brown oil in 8.6 g. It was dissolvedin 125 ml THF and 125 ml 1.5N HCl solution. The resulting solution wasstirred at reflux for 1 h. THF was evaporated and residue was dilutedwith H₂O and ethyl acetate. The aqueous layer was extracted with ethylacetate. The combined organic layer was washed with 5% NaHCO₃ solution,brine, dried with MgSO₄, and concentrated to afford a yellow oil in 7.8g. This product was used without further purification. NMR spectra ofthe product were consistent for the proposed structure.

[0426] Step 6

[0427] A solution of silver nitrate (13.9 g, 82.0 mmol) in 20 ml H₂O wasadded to a solution of the product of step 5 (7.8 g, 41.0 mmol) in 200ml ethanol. A solution of Sodium hydroxide (6.6 g, 164.0 mmol) in 10 mlH₂O was added dropwise at room temperature. After 2 h, the reaction wasfiltered through a short column of Celite®. The filtrate was dilutedwith H₂O and extracted with ether (3×30 ml). The aqueous layer wasacidified with concentrated HCl and extracted with chloroform. Thechloroform layer was dried with MgSO₄ and concentrated. The residue wasdissolved in 150 ml ethanol and 50 ml 4N HCl in dioxane. The resultingreaction solution was stirred at room temperature for 18 h andconcentrated to afford a brown oil in 7.88 g. This product was usedwithout further purification. NMR spectra of the product were consistentfor the proposed structure.

[0428] Step 7 Boron tribromide solution (40 ml, 40 mmol, 1 M indichloromethane) was added to a solution of the product of step 6 (7.8g, 32.9 mmol) in 50 ml dichloromethane dropwise at 0° C. The resultingreaction solution was allowed to warm to room temperature. After 30 min,the reaction was carefully quenched with ethanol. The product wasextracted with ethyl acetate and washed with 1N HCl. The organic layerwas further washed with 5% NaHCO₃ solution, brine, and dried with MgSO₄,and concentrated. The residue was purified by chromatography (on silicagel, ethyl acetate/hexane=1/3) to give a pale brown oil in 3.84 g. NMRspectra of the product were consistent for the proposed structure.

[0429] Step 8

[0430] A solution of diethyl azodicarboxylate (348 mg, 2.0 mmol) in 2 mlTHF was added to a solution of the product of step 7 (275 mg, 1.25 mmol)and triphenylphosphine (525 mg, 2.0 mmol) in 10 ml THF at roomtemperature and stirred for 15 min. 6-(methylamino)-2-pyridyl ethanol(304 mg, 2.0 mmol) was added. The resulting reaction mixture was stirredat room temperature for 3 h. THF was evaporated and the residue waspurified by chromatography (on silica gel, ethyl acetate/hexane=1/1) toyield a solid in 500 mg. NMR spectra of the product were consistent forthe proposed structure.

[0431] Step 9

[0432] The product of step 8 (500 mg, 1.4 mmol) was dissolved in 25 mlmethanol and 25 ml 1N sodium hydroxide solution. The reaction wasstirred at room temperature for 18 h, acidified with 4 mltrifluoroacetic acid, and concentrated. The residue was purified on HPLCusing acetonitrile gradient 15-50% in 30 min to yield 200 mg.FAB-MS:(MH+)=327.4.H NMR (CDCl3) δ 0.82 (dt, 1H), 0.94 (dt, 1H), 1.3 (m,1H), 1.73 (dt, 1lH), 2.43 (d, 2H), 2.97 (s, 3H), 3.23 (t, 2H), 4.29 (t,2H), 6.59 (d, 1H), 6.68 (d, 1H), 6.80 (d, 2H), 7.02 (d, 2H), 7.73 (dd,1H), 9.84 (br, 1H). Anal Calcd. for C₁₉H₂₂N₂O₃ plus 1.45 CF₃COOH: C,53.49;H, 4.81; N, 5.70. Found: 53.64;H, 5.06; N, 5.92.

EXAMPLE 12 2-[4-[2-(3,4-dihydro-2H-pyrido[3,2-b]-1,4-oxazin-6-yl)ethoxy]phenyl]-cyclopropaneacetic Acid

[0433]

[0434] Step 1

[0435] 2-amino-6-methyl-3-pyridinol

[0436] 3-Hydroxy-6-methyl-2-nitropyridine (30 g, 194.6 mmol) washydrogenated in ethanol solution at 50° C. using H₂ at 5 psi and 20%Pd(OH)₂/C catalyst for 1 hour. Upon completion of the reaction, thecatalyst was filtered off and the filtrate was concentrated underreduced pressure to get the desired product 1 as a brown solid (23.68 g,98%). NMR data was consistent with the proposed structure.

[0437] Step 2

[0438] 6-methyl-2H-pyrido[3,2-b]-1,4-oxazin-3(4h)-one

[0439] chloroacetyl chloride (0.37 mL) was added dropwise to a stirred,cooled (0° C.) mixture of 1 (0.500 g), 0.810 g NaHCO₃, and 4 mL2-butanone in 4 mL water. Once the addition was complete, the reactionmixture was warmed to room temp. and stirred for 30 minutes, then heatedto 75° C. for 2 hours. The reaction mixture was cooled to room temp. andthe 2-butanone was stripped off under reduced pressure. 1 mL water wasadded and the solids were filtered off and washed with water to get thecrude product. The solid was dissolved in warmed (50° C.) ethyl acetateand filtered through a small plug of silica gel. The silica gel waswashed with more warm ethyl acetate, combined with the filtrate, andconcentrated under reduced pressure to get the desired product 2 (0.250g, 38%) as a deep orange solid. NMR data was consistent with theproposed structure.

[0440] Step 3

[0441] Synthesis of 3,4-dihydro-6-methyl-2H-pyrido[3,2-b]-1,4-oxazine

[0442] LiAlH₄ (0.289 g) was slowly added to 15 mL dry THF in around-bottom flask fitted with a stirbar and a condenser. After stirringfor 10 minutes, a solution of 2 (1.00 g) in 15 mL dry THF was addeddropwise. Upon completion of the addition, the reaction mixture wasrefluxed for 16 hours. The reaction was cooled to room temp. andquenched with 1 M NaOH solution until the mixture had become a milkyyellow color. The precipitate was filtered off and washed 3 times withCH₂Cl₂. The filtrate and washings were combined, washed with brine,dried over MgSO₄, and concentrated under reduced pressure to get 3(0.910 g, 99%) as a pale yellow oil, which solidified on standing. NMRdata was consistent with the proposed structure.

[0443] Step 4

[0444] 2,3-dihydro-6-methyl-4H-pyrido[3,2-b]-1,4-oxazine-4-carboxylicacid, 1,1-dimethylethyl Ester

[0445] A solution of 3 (2.96 g), di-tert-butyl dicarbonate (4.302 g) andtriethylamine (2.75 mL) in 35 mL DMF was warmed to 50° C. with stirringfor 16 hours. The reaction mixture was allowed to cool to room temp. andwas concentrated under reduced pressure to get the crude product, whichwas purified by chromatography on silica gel (eluent: 30/70 ethylacetate/hexane). The desired fractions were combined and concentratedunder reduced pressure to get the desired product 4 (1.46 g, 30%) as ayellow oil. NMR data was consistent with the proposed structure.

[0446] Step 5

[0447]4-[(1,1-dimethylethoxy)carbonyl]-3,4-dihydro-2H-pyrido[3,2-b]-1,4-oxazine-6-aceticAcid, Ethyl Ester

[0448] Lithium diisopropylamide solution (8.17 Ml, 2.0 M inTHF/ethylbenzene/heptane) was added dropwise to a chilled (−78° C.),stirred solution of 4 (1.46 g) and diethyl carbonate (2.549 g) in 15 mLdry THF under nitrogen atmosphere. After 30 minutes the reaction wasquenched with saturated NH₄Cl solution and warmed to room temp. Themixture was extracted three times with ethyl acetate and all organicextracts were combined, dried over MgSO₄, and concentrated under reducedpressure to get the crude product, which was purified by chromatographyon silica gel (eluent: 40/60 ethyl acetate/hexane). The desiredfractions were combined and concentrated under reduced pressure to getthe desired product 5 (1.48 g, 78%) as a yellow solid. NMR data wasconsistent with the proposed structure.

[0449] Step 6

[0450] 3,4-dihydro-2H-pyrido[3,2-b]-1,4-oxazine-6-ethanol

[0451] To a solution of 5 (1.48 g) in dry THF (20 mL) at room temp. wasadded a solution of LiBH₄ (2.0 M in THF, 2.75 mL), and the resultingmixture was heated to reflux. After 16 hours the mixture was cooled to0° C. and carefully quenched with water (20 mL). After 10 minutes, themixture was extracted three times with ethyl acetate. The combinedorganic extracts were dried over MgSO₄, filtered, and concentrated underreduced pressure. This residue was dissolved in CH₂Cl₂ (3 mL), and tothis solution was added 4 M HCl in dioxane (6 mL) all at once at roomtemp. After 4 hours, the mixture was concentrated under reduced pressureto get the crude product, which was chromatographed on silica gel(eluent: 94.5/5/0.5 chloroform/ethanol/ammonium hydroxide). The desiredfractions were combined and concentrated under reduced pressure to getthe desired product 6 (0.364 g, 44%) as a pale yellow solid. HMNR(CDCl3) δ 2.78 (t, 2H), 3.55 (m, 2H), 3.92 (t, 2H), 4.23 (m, 2H),6.40 (d, 2H), 6.90 (d, 2H).

[0452] Step 7

[0453]2-[4-[2-(3,4-dihydro-2H-pyrido[3,2-b]-1,4-oxazin-6-yl)ethoxy]phenyl]cyclopropaneaceticAcid, Ethyl Ester

[0454] A solution of diethyl azodicarboxylate (348 mg, 2.0 mmol) in 2 mlTHF was added to a solution of the product of step 8, EXAMPLE 11 (366mg, 1.66 mmol) and triphenylphosphine (525 mg, 2.0 mmol) in 10 ml THF atroom temperature and stirred for 15 min. The product of step 6 (360 mg,2.0 mmol) was added. The resulting reaction mixture was stirred at roomtemperature for 3 h. THF was evaporated and the residue was purified bychromatography (on silica gel, CH₂Cl₂/CH₃OH/NH₄OH 98.5/1/0.5) to yieldan yellow oil in 380 mg. NMR spectra of the product were consistent forthe proposed structure.

[0455] Step 8

[0456]2-[4-[2-(3,4-dihydro-2H-pyrido[3,2-b]-1,4-oxazin-6-yl)ethoxy]phenyl]cyclopropaneaceticAcid

[0457] The product of step 7 (380 mg, 1 mmol) was dissolved in 5 mlmethanol and 2.5 ml 1N sodium hydroxide solution. The reaction wasstirred at room temperature for 18 h, acidified with 1 mltrifluoroacetic acid, and concentrated. The residue was purified on HPLCusing acetonitrile gradient 15-50% in 30 min to yield 210 mg desiredproduct as an yellow oil. FAB-MS:(MH+)=355.H MNR(CDCl3) δ 0.78 (m, 1H),0.86 (m, 1H), 1.21 (m, 1H), 1.70 (m, 1H), 2.35 (m, 2H), 3.12 (t, 2H),3.63 (t, 2H), 4.22 (t, 2H), 4.26 (t, 2H), 6.65 (d, 1H), 6.79 (d, 2H),7.0 (d, 2H), 7.6 (d, 1H). Anal Calcd. for C₂₀H₂₂N₂O₄ plus 1 CF₃COOH and0.2H₂O: C, 55.98;H, 5.00; N, 5.93. Found: 55.90;H, 5.28; N, 5.24.

EXAMPLE 13 3-[4-[3-(2-pyridinylamino)propoxy]phenyl]cyclobutaneaceticAcid

[0458]

[0459] The compounds of Formula 1 containing a cyclobutyl with a1,3-substituion can be synthesized as shown in the above scheme. Forexample, reaction of 4-methoxystyrene with in-situ generateddichloroketene gives the cycloadduct which can be dehalogenated to givethe cyclobutanone derivative shown in Step 2. The reaction described inTetrahedron Asymmetry 10, 2113-2118, 1999 for other substituted styrenescan be used to accomplish their synthesis. Elaboration of thisintermediate involving Horner-Emmons reaction, reduction of olefin,demethylation, Mitsunobu reaction, deoxygenation and hydrolysis of estergives the target compound. The experimental conditions described inSteps 2-7, in Example 2 can be used to achieve the synthesis of targetcompound.

EXAMPLE 14(1-Methyl-2-{4-[3-(pyridin-2-ylamino)-propoxyl]-phenyl}-cyclopropyl)-aceticAcid

[0460]

[0461] The title compound was prepared starting with benzaldehyde andtriethylphosphonopropionoate following the reaction sequence shown inscheme 8. ¹H MNR(CDCl₃) δ 0.83 (t, 1H), 0.86 (s, 3H), 0.93 (dd, 1H),2.05 (dd, 1lH), 2.19 (p, 2H), 2.29 (d, 1H), 2.57 (d, 1H), 2.57 (d, 1H),3.53 (q, 2H), 4.05 (t, 2H), 6.70 (t, 1H), 6.81 (d, 2H), 6.85 (d, 1H),7.15 (d, 2H), 7.73 (ddd, 1H), 7.80 (d, 1H), 9.70 (br, 1H); MS (ESI) m/z=341 (MH+); Anal Calcd. for C₂₀H₂₄N₂O₃.1.65 CF₃COOH: C, 52.95;H, 4.89;N, 5.30. Found: 52.90;H, 4.95; N, 5.36.

EXAMPLE 15(1-Methyl-2-{4-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-phenyl}-cyclopropyl)-aceticAcid

[0462]

[0463] The title compound was prepared starting with benzaldehyde andtriethylphosphonopropionoate following the reaction sequence shown inscheme 8. ¹H MNR(CDCl₃) δ 0.83 (t, 1H), 0.86 (s, 3H), 0.92 (dd, 1H),1.94 (p, 2H), 2.04 (dd, 1lH), 2.29 (d, 1H), 2.55 (d, 1H), 2.76 (t, 2H),3.18 (t, 2H), 3.52 (t, 2H), 4.29 (t, 2H), 6.00 (brs, 2H), 6.53 (d, 1H),6.82 (d, 2H), 7.15 (d, 2H), 7.34 (d, 1H), 9.64 (br, 1H); Anal Calcd. forC₂₂H₂₆N₂O₃.0.1.5 CF₃COOH: C, 56.81;H, 5.50; N, 5.42. Found: 57.13;H,5.50; N, 5.08.

EXAMPLE 16(2-{2-Methoxy-4-[3-(pyridin-2-ylamino)-propoxy]-phenyl}-cyclopropyl)-aceticAcid

[0464]

[0465] The title compound is prepared according to the generalprocedures described in SCHEME 11.

EXAMPLE 17[1-Methyl-2-(4-{2-[6-(2,2,2-trifluoro-ethylamino)-pyridin-2-yl]-ethoxy}-phenyl)-cyclopropyl]-aceticAcid

[0466]

[0467] The title compound is prepared according to the generalprocedures described in SCHEME 10.

EXAMPLE 18(2-{4-[2-(6-Ethylamino-pyridin-2-yl)-ethoxy]-phenyl}-cyclopropyl)-aceticAcid

[0468]

[0469] The title compound is prepared according to the generalprocedures described in SCHEME 10.

EXAMPLE 19[2-(4-{2-[6-(2-Methoxy-ethylamino)-pyridin-2-yl]-ethoxy}-phenyl)-cyclopropyl]-aceticAcid

[0470]

[0471] The title compound is prepared according to the generalprocedures described in SCHEME 10.

EXAMPLE 20[2-(4-{2-[6-(2,2,2-Trifluoro-ethylamino)-pyridin-2-yl]-ethoxy}-phenyl)-cyclopropyl]-aceticAcid

[0472]

[0473] The title compound is prepared according to the generalprocedures described in SCHEME 10.

EXAMPLE 21[2-(4-{2-[6-(3-Methoxy-propylamino)-pyridin-2-yl]-ethoxy}-phenyl)-cyclopropyl]-aceticAcid

[0474]

[0475] The title compound is prepared according to the generalprocedures described in SCHEME 10.

EXAMPLE 22(2-{2-Fluoro-4-[3-(pyridin-2-ylamino)-propoxy]-phenyl}-cyclopropyl)-aceticAcid

[0476]

[0477] The title compound is prepared according to the generalprocedures described in SCHEME11.

EXAMPLE 23(2-{2-Acetoxy-4-[3-(pyridin-2-ylamino)-propoxy]-phenyl}-cyclopropyl)-aceticAcid

[0478]

[0479] The title compound is prepared according to the generalprocedures described in SCHEME11.

EXAMPLE 24(1-Methoxymethyl-2-{4-[3-(pyridin-2-ylamino)-propoxy]-phenyl}-cyclopropyl)-aceticAcid

[0480]

[0481] The title compound is prepared according to the generalprocedures described in SCHEME 8.

EXAMPLE 25(1-Methanesulfonylmethyl-2-{4-[3-(pyridin-2-ylamino)-propoxy]-phenyl}-cyclopropyl)-aceticAcid

[0482]

[0483] The title compound is prepared according to the generalprocedures described in SCHEME 8.

EXAMPLE 26(1-Pyridin-3-yl-2-{4-[3-(pyridin-2-ylamino)-propoxy]-phenyl}-cyclopropyl)-aceticAcid

[0484]

[0485] The title compound is prepared according to the generalprocedures described in SCHEME 8.

EXAMPLE 27(1-Benzo[1,3]dioxol-5-yl-2-{4-[3-(pyridin-2-ylamino)-propoxy]-phenyl}-cyclopropyl)-aceticAcid

[0486]

[0487] The title compound is prepared according to the generalprocedures described in SCHEME 8.

EXAMPLE 28(1-(2,3-Dihydro-benzofuran-6-yl)-2-{4-[3-(pyridin-2-ylamino)-propoxy]-phenyl}-cyclopropyl)-aceticAcid

[0488]

[0489] The title compound is prepared according to the generalprocedures described in SCHEME 8.

EXAMPLE 29(1-Isoxazol-3-yl-2-{4-[3-(pyridin-2-ylamino)-propoxy]-phenyl}-cyclopropyl)-aceticAcid

[0490]

[0491] The title compound is prepared according to the generalprocedures described in SCHEME 8.

EXAMPLE 30(1-Isoxazol-5-yl-2-{4-[3-(pyridin-2-ylamino)-propoxy]-phenyl}-cyclopropyl)-aceticAcid

[0492]

[0493] The title compound is prepared according to the generalprocedures described in SCHEME 8.

EXAMPLE 31(1-Oxazol-5-yl-2-{4-[3-(pyridin-2-ylamino)-propoxy]-phenyl}-cyclopropyl)-aceticAcid

[0494]

[0495] The title compound is prepared according to the generalprocedures described in SCHEME 8.

EXAMPLE 32(2-{4-[3-(Pyridin-2-ylamino)-propoxy]-phenyl}-1-thiazol-5-yl-cyclopropyl)-aceticAcid

[0496]

[0497] The title compound is prepared according to the generalprocedures described in SCHEME 8.

EXAMPLE 33(1-Methoxymethyl-2-{4-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-phenyl}-cyclopropyl)-aceticAcid

[0498]

[0499] The title compound is prepared according to the generalprocedures described in SCHEME 8.

EXAMPLE 34(1-Methanesulfonylmethyl-2-{4-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-phenyl}-cyclopropyl)-aceticAcid

[0500]

[0501] The title compound is prepared according to the generalprocedures described in SCHEME 8.

EXAMPLE 35(1-Pyridin-3-yl-2-{4-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-phenyl}-cyclopropyl)-aceticacid

[0502]

[0503] The title compound is prepared according to the generalprocedures described in SCHEME 8.

EXAMPLE 36(1-(2,3-Dihydro-benzofuran-6-yl)-2-{4-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-phenyl}-cyclopropyl)-aceticAcid

[0504]

[0505] The title compound is prepared according to the generalprocedures described in SCHEME 8.

EXAMPLE 37(1-Benzo[1,3]dioxol-5-yl-2-{4-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-phenyl}-cyclopropyl)-aceticAcid

[0506]

[0507] The title compound is prepared according to the generalprocedures described in SCHEME 8.

EXAMPLE 38(1-Isoxazol-3-yl-2-{4-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-phenyl}-cyclopropyl)-aceticAcid

[0508]

[0509] The title compound is prepared according to the generalprocedures described in SCHEME 8.

EXAMPLE 39(1-Isoxazol-5-yl-2-{4-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-phenyl}-cyclopropyl)-aceticAcid

[0510]

[0511] The title compound is prepared according to the generalprocedures described in SCHEME 8.

EXAMPLE 40(1-Oxazol-5-yl-2-{4-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-phenyl}-cyclopropyl)-aceticAcid

[0512]

[0513] The title compound is prepared according to the generalprocedures described in SCHEME 8.

EXAMPLE 41(2-{4-[2-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-phenyl}-1-thiazol-5-yl-cyclopropyl)-aceticAcid

[0514]

[0515] The title compound is prepared according to the generalprocedures described in SCHEME 8.

EXAMPLE 42(2-{4-[3-(1-H-Imidazol-2-ylamino)-propoxy]-phenyl}-cyclopropyl)-aceticAcid

[0516]

[0517] The title compound is prepared according to the generalprocedures described in SCHEME 9.

EXAMPLE 43(2-{3-Fluoro-4-[3-(1-H-imidazol-2-ylamino)-propoxy]-phenyl}-cyclopropyl)-aceticAcid

[0518]

[0519] The title compound is prepared according to the generalprocedures described in SCHEME 9.

EXAMPLE 44(2-{3-Fluoro-4-[3-(3-H-imidazol-4-ylamino)-propoxy]-phenyl}-cyclopropyl)-aceticAcid

[0520]

[0521] The title compound is prepared according to the generalprocedures described in SCHEME 9.

EXAMPLE 45(2-{4-[3-(3-H-imidazol-4-ylamino)-propoxy]-phenyl}-cyclopropyl)-aceticAcid

[0522]

[0523] The title compound is prepared according to the generalprocedures described in SCHEME 9.

EXAMPLE 46(2-{4-[3-(1-H-Pyrazol-3-ylamino)-propoxy]-phenyl}-cyclopropyl)-aceticAcid

[0524]

[0525] The title compound is prepared according to the generalprocedures described in SCHEME 9.

EXAMPLE 47(2-{3-Fluoro-4-[3-(1-H-pyrazol-3-ylamino)-propoxy]-phenyl}-cyclopropyl)-aceticAcid

[0526]

[0527] The title compound is prepared according to the generalprocedures described in SCHEME 9.

EXAMPLE 48(1-Methyl-2-{4-[2-(6-methylamino-pyridin-2-yl)-ethoxy]-phenyl}-cyclopropyl)-aceticAcid

[0528]

[0529] The title compound is prepared according to the generalprocedures described in SCHEME 10.

EXAMPLE 49(2-{4-[2-(6-Ethylamino-pyridin-2-yl)-ethoxy]-phenyl}-1-methyl-cyclopropyl)-aceticAcid

[0530]

[0531] The title compound is prepared according to the generalprocedures described in SCHEME 10.

EXAMPLE 50[2-(4-{2-[6-(2-Methoxy-ethylamino)-pyridin-2-yl]-ethoxy}-phenyl)-1-methyl-cyclopropyl]-aceticAcid

[0532]

[0533] The title compound is prepared according to the generalprocedures described in SCHEME 10.

EXAMPLE 51[2-(4-{2-[6-(3-Methoxy-propylamino)-pyridin-2-yl]-ethoxy}-phenyl)-1-methyl-cyclopropyl]-aceticAcid

[0534]

[0535] The title compound is prepared according to the generalprocedures described in SCHEME 10.

EXAMPLE 52(2-{4-[2-(6-Acetylamino-pyridin-2-yl)-ethoxy]-phenyl}-1-methyl-cyclopropyl)-aceticAcid

[0536]

[0537] The title compound is prepared according to the generalprocedures described in SCHEME 10.

EXAMPLE 53(2-{4-[2-(6-Acetylamino-pyridin-2-yl)-ethoxy]-phenyl}-cyclopropyl)-aceticAcid

[0538]

[0539] The title compound is prepared according to the generalprocedures described in SCHEME 10.

[0540] The activity of the compounds of the present invention was testedin the following assays.

Vitronectin Adhesion Assay

[0541] Materials

[0542] Human vitronectin receptors α_(V)β₃ and α_(V)β₅ were purifiedfrom human placenta as previously described [Pytela et al., Methods inEnzymology, 144:475-489 (1987)]. Human vitronectin was purified fromfresh frozen plasma as previously described [Yatohgo et al., CellStructure and Function, 13:281-292 (1988)]. Biotinylated humanvitronectin was prepared by coupling NHS-biotin from Pierce ChemicalCompany (Rockford, Ill.) to purified vitronectin as previously described[Charo et al., J. Biol. Chem., 266(3):1415-1421 (1991)]. Assay buffer,OPD substrate tablets, and RIA grade BSA were obtained from Sigma (St.Louis, Mo.). Anti-biotin antibody was obtained from Sigma (St. Luois,Mo.). Nalge Nunc-lmmuno microtiter plates were obtained from NalgeCompany (Rochester, N.Y.).

Methods Solid Phase Receptor Assays

[0543] This assay was essentially the same as previously reported [Niiyaet al., Blood, 70:475-483 (1987)]. The purified human vitronectinreceptors α_(V)β₃ and α_(V)β₅ were diluted from stock solutions to 1.0μg/mL in Tris-buffered saline containing 1.0 mM Ca⁺⁺, Mg⁺⁺, and Mn⁺⁺, pH7.4 (TBS⁺⁺⁺). The diluted receptors were immediately transferred toNalge Nunc-lmmuno microtiter plates at 100 μL/well (100 ngreceptor/well). The plates were sealed and incubated overnight at 4° C.to allow the receptors to bind to the wells. All remaining steps were atroom temperature. The assay plates were emptied and 200 μL of 1% RIAgrade BSA in TBS⁺⁺⁺ (TBS⁺⁺⁺/BSA) were added to block exposed plasticsurfaces. Following a 2 hour incubation, the assay plates were washedwith TBS⁺⁺⁺ using a 96 well plate washer. Logarithmic serial dilution ofthe test compound and controls were made starting at a stockconcentration of 2 mM and using 2 nM biotinylated vitronectin inTBS⁺⁺⁺/BSA as the diluent. This premixing of labeled ligand with test(or control) ligand, and subsequent transfer of 50 μL aliquots to theassay plate was carried out with a CETUS Propette robot; the finalconcentration of the labeled ligand was 1 nM and the highestconcentration of test compound was 1.0×10⁻⁴ M. The competition occurredfor two hours after which all wells were washed with a plate washer asbefore. Affinity purified horseradish peroxidase labeled goatanti-biotin antibody was diluted 1:2000 in TBS⁺⁺⁺/BSA and 125 μL wasadded to each well. After 45 minutes, the plates were washed andincubated with OPD/H₂O₂ substrate in 100 mM/L Citrate buffer, pH 5.0.The plate was read with a microtiter plate reader at a wavelength of 450nm and when the maximum-binding control wells reached an absorbance ofabout 1.0, the final A₄₅₀ were recorded for analysis. The data wereanalyzed using a macro written for use with the EXCEL spreadsheetprogram. The mean, standard deviation, and %CV were determined forduplicate concentrations. The mean A₄₅₀ values were normalized to themean of four maximum-binding controls (no competitor added)(B-MAX). Thenormalized values were subjected to a four parameter curve fit algorithm[Rodbard et al., Int. Atomic Energy Agency, Vienna, pp 469 (1977)],plotted on a semi-log scale, and the computed concentrationcorresponding to inhibition of 50% of the maximum binding of 2biotinylated vitronectin (IC₅₀) and corresponding R² was reported forthose compounds exhibiting greater than 50% inhibition at the highestconcentration tested; otherwise the IC₅₀ is reported as being greaterthan the highest concentration tested.β-[[2-[[5-[(aminoiminomethyl)amino]-1-oxopentyl]amino]-1-oxoethyl]amino]-3-pyridinepropanoicacid [U.S. Pat. No. 5,602,155 Example 1] which is a potent α_(V)β₃antagonist (IC₅₀ in the range 3-10 nM) was included on each plate as apositive control.

PURIFIED IIb/IIIa RECEPTOR ASSAY

[0544] Materials

[0545] Human fibrinogen receptor (IIb/IIIa) was purified from outdatedplatelets. (Pytela, R., Pierschbacher, M. D., Argraves, S., Suzuki, S.,and Rouslahti, E. “Arginine-Glycine-Aspartic acid adhesion receptors”,Methods in Enzymology 144(1987):475-489.) Human vitronectin was purifiedfrom fresh frozen plasma as described in Yatohgo, T., Izumi, M.,Kashiwagi, H., and Hayashi, M., “Novel purification of vitronectin fromhuman plasma by heparin affinity chromatography,” Cell Structure andFunction 13(1988):281-292. Biotinylated human vitronectin was preparedby coupling NHS-biotin from Pierce Chemical Company (Rockford, Ill.) topurified vitronectin as previously described. (Charo, I. F., Nannizzi,L., Phillips, D. R., Hsu, M. A., Scarborough, R. M., “Inhibition offibrinogen binding to GP IIb/IIIa by a GP IIIa peptide”, J. Biol. Chem.266(3)(1991): 1415-1421.) Assay buffer, OPD substrate tablets, and RIAgrade BSA were obtained from Sigma (St. Louis, Mo.). Anti-biotinantibody was obtained from Sigma (St. Louis, Mo.). Nalge Nunc-immunomicrotiter plates were obtained from (Rochester, N.Y.). ADP reagent wasobtained from Sigma (St. Louis, Mo.).

Methods

[0546] Solid Phase Receptor Assays

[0547] This assay is essentially the same reported in Niiya, K., Hodson,E., Bader, R., Byers-Ward, V. Koziol, J. A., Plow, E. F. and Ruggeri, Z.M., “Increased surface expression of the membrane glycoprotein IIb/IIIacomplex induced by platelet activation: Relationships to the binding offibrinogen and platelet aggregation”, Blood 70(1987):475-483. Thepurified human fibrinogen receptor (IIb/IIIa) was diluted from stocksolutions to 1.0 μg/mL in Tris-buffered saline containing 1.0 mM Ca⁺⁺,Mg⁺⁺, and Mn⁺⁺, pH 7.4 (TBS⁺⁺⁺). The diluted receptor was immediatelytransferred to Nalge Nunc-Immuno microtiter plates at 100 μL/well (100ng receptor/well). The plates were sealed and incubated overnight at 4°C. to allow the receptors to bind to the wells. All remaining steps wereat room temperature. The assay plates were emptied and 200 μL of 1% RIAgrade BSA in TBS⁺⁺⁺ (TBS⁺⁺⁺/BSA) were added to block exposed plasticsurfaces. Following a 2 hour incubation, the assay plates were washedwith TBS⁺⁺⁺ using a 96 well plate washer. Logarithmic serial dilution ofthe test compound and controls were made starting at a stockconcentration of 2 mM and using 2 nM biotinylated vitronectin inTBS⁺⁺⁺/BSA as the diluent. This premixing of labeled ligand with test(or control) ligand, and subsequent transfer of 50 μL aliquots to theassay plate was carried out with a CETUS Propette robot; the finalconcentration of the labeled ligand was 1 nM and the highestconcentration of test compound was 1.0×10⁻⁴ M. The competition occurredfor two hours after which all wells were washed with a plate washer asbefore. Affinity purified horseradish peroxidase labeled goatanti-biotin antibody was diluted 1:2000 in TBS⁺⁺⁺/BSA and 125 μL wereadded to each well. After 45 minutes, the plates were washed andincubated with ODD/H₂O₂ substrate in 100 mM/L citrate buffer, pH 5.0.The plate was read with a microtiter plate reader at a wavelength of 450nm and when the maximum-binding control wells reached an absorbance ofabout 1.0, the final A₄₅₀ were recorded for analysis. The data wereanalyzed using a macro written for use with the EXCELJ spreadsheetprogram. The mean, standard deviation, and %CV were determined forduplicate concentrations. The mean A₄₅₀ values were normalized to themean of four maximum-binding controls (no competitor added)(B-MAX). Thenormalized values were subjected to a four parameter curve fitalgorithm, [Robard et al., Int. Atomic Energy Agency Vienna, pp 469(1977)], plotted on a semi-log scale, and the computed concentrationcorresponding to inhibition of 50% of the maximum binding ofbiotinylated vitronectin (IC₅₀) and corresponding R² was reported forthose compounds exhibiting greater than 50% inhibition at the highestconcentration tested; otherwise the IC₅₀ is reported as being greaterthan the highest concentration tested.β-[[2-[[5-[(aminoiminomethyl)amino]-1-oxopentyl]amino]-1-oxoethyl]amino]-3-pyridinepropanoicacid [U.S. Pat. No. 5,602,155 Example 1] which is a potent α_(V)β₃antagonist (IC₅₀ in the range 3-10 nM) was included on each plate as apositive control.

Human Platelet Rich Plasma Assays

[0548] Healthy aspirin free donors were selected from a pool ofvolunteers. The harvesting of platelet rich plasma and subsequent ADPinduced platelet aggregation assays were performed as described inZucker, M. B., “Platelet Aggregation Measured by the PhotometricMethod”, Methods in Enzymology 169(1989):117-133. Standard venipuncturetechniques using a butterfly allowed the withdrawal of 45 mL of wholeblood into a 60 mL syringe containing 5 mL of 3.8% trisodium citrate.Following thorough mixing in the syringe, the anti-coagulated wholeblood was transferred to a 50 mL conical polyethylene tube. The bloodwas centrifuged at room temperature for 12 minutes at 200× g to sedimentnon-platelet cells. Platelet rich plasma was removed to a polyethylenetube and stored at room temperature until used. Platelet poor plasma wasobtained from a second centrifugation of the remaining blood at 2000× gfor 15 minutes. Platelet counts are typically 300,000 to 500,000 permicroliter. Platelet rich plasma (0.45 mL) was aliquoted intosiliconized cuvettes and stirred (1100 rpm) at 37° C. for 1 minute priorto adding 50 uL of pre-diluted test compound. After 1 minute of mixing,aggregation was initiated by the addition of 50 uL of 200 uM ADP.Aggregation was recorded for 3 minutes in a Payton dual channelaggregometer (Payton Scientific, Buffalo, N.Y.). The percent inhibitionof maximal response (saline control) for a series of test compounddilutions was used to determine a dose response curve. All compoundswere tested in duplicate and the concentration of half-maximalinhibition (IC₅₀) was calculated graphically from the dose responsecurve for those compounds which exhibited 50% or greater inhibition atthe highest concentration tested; otherwise, the IC₅₀ is reported asbeing greater than the highest concentration tested.

What is claimed is:
 1. A compound of the formula

or a pharmaceutically acceptable salt thereof, wherein

is a 4-8 membered monocyclic ring or 7-12 membered bicyclic ring; whichring is optionally saturated or unsaturated, which ring is optionallysubstituted with one or more substituent selected from the groupconsisting of alkyl, haloalkyl, aryl, heteroaryl, halogen, alkoxyalkyl,aminoalkyl, hydroxy, nitro, alkoxy, hydroxyalkyl, thioalkyl, amino,alkylamino, arylamino, alkylsulfonamide, acyl, acylamino, alkylsulfone,sulfonamide, allyl, alkenyl, methylenedioxy, ethylenedioxy, alkynyl,carboxamide, cyano, and —(CH₂)_(n) COR wherein n is 0-2 and R ishydroxy, alkoxy, alkyl or amino; A¹ is a 5-9 membered monocyclic or 7-14membered polycyclic heterocycle of the formula

 containing at least one nitrogen atom and optionally 1 to 4 heteroatomsor groups, selected from O, N, S, SO₂ or CO; optionally saturated orunsaturated; optionally substituted by one or more R^(k) selected fromthe group consisting of hydroxy, alkyl, alkoxy, alkoxyalkyl, thioalkyl,haloalkyl, cyano, amino, alkylamino, halogen, acylamino, sulfonamide and—COR wherein R is hydroxy, alkoxy, alkyl or amino;

 include the following heterocyclic ring systems containing at least onenitrogen atom:

 wherein Z_(a) is H, alkyl, alkoxy, hydroxy, amine, alkylamine,dialkylamine, carboxyl, alkoxycarbonyl, hydroxyalkyl, halogen orhaloalkyl and R¹ is H, alkyl, alkoxyalkyl, acyl, haloalkyl oralkoxycarbonyl, pyridylamino, imidazolylamino, morpholinopyridine,tetrahydronaphthyridine, oxazolylamino, thiazolylamino,pyrimidinylamino, quinoline, isoquinoline, tetrahydroquinoline,imidazopyridine, benzimidazole, pyridone or quinolone; The followingheteroaryls include the ring systems described above;

 for the pyridyl derived heterocycle, the substituents X₄ and X₅ areselected from the group consisting of H, alkyl, branched alkyl,alkylamino, alkoxyalkylamino, haloalkyl, thioalkyl, halogen, amino,alkoxy, aryloxy, alkoxyalkyl, hydroxy, cyano or acylamino groups;substituents X₄ and X₅ can be methyl, methoxy, amine, methylamine,trifluoromethyl, dimethylamine, hydroxy, chloro, bromo, fluoro andcyano. X₆ may be H, alkyl, halogen, alkoxy, hydroxy, and haloalkyl; thepyridyl ring can be fused with a 4-8 membered ring, optionally saturatedor unsaturated; these ring systems include tetrahydronaphthyridine,quinoline, tetrahydroquinoline, azaquinoline, morpholinopyridine,imidazo-pyridine; the monocyclic ring systems such as imidazole,thiazole, oxazole, pyrazole may contain an amino or alkylaminosubstituent at any position within the ring; when Z₁ of Formula I is COor SO₂, the linkage A¹-Z₂ of Formula I includes the heterocycle derivedring systems: pyridine, imidazole, thiazole, oxazole, benzimidazole,imidazopyridine and heterocycles for A¹-Z₂ include:

 wherein X₄ is as defined above. or A¹ is

wherein Y¹ is selected from the group consisting of N—R², O, and S; R²isselected from the group consisting of H; alkyl; aryl; hydroxy; alkoxy;cyano; alkenyl; alkynyl; amido; alkylcarbonyl; arylcarbonyl;alkoxycarbonyl; aryloxycarbonyl; haloalkylcarbonyl; haloalkoxycarbonyl;alkylthiocarbonyl; arylthiocarbonyl; acyloxymethoxycarbonyl; R² takentogether with R⁷ forms a 4-12 membered dinitrogen containing heterocycleoptionally substituted with one or more substituent selected from thegroup consisting of lower alkyl, thioalkyl, alkylamino, hydroxy, keto,alkoxy, halo, phenyl, amino, carboxyl or carboxyl ester, and fusedphenyl; or R² taken together with R⁷ forms a 4-12 membered heterocyclecontaining one or more heteroatom selected from O, N and S optionallyunsaturated; or R² taken together with R⁷ forms a 5 memberedheteroaromatic ring fused with a aryl or heteroaryl ring; R⁷ (when nottaken together with R²) and R⁸ are independently selected from the groupconsisting of H; alkyl; alkenyl; alkynyl; aralkyl; amino; alkylamino;hydroxy; alkoxy; arylamino; amido, alkylcarbonyl, arylcarbonyl;alkoxycarbonyl; aryloxy; aryloxycarbonyl; haloalkylcarbonyl;haloalkoxycarbonyl; alkylthiocarbonyl; arylthiocarbonyl;acyloxymethoxycarbonyl; cycloalkyl; bicycloalkyl; aryl; acyl; benzoyl;or NR⁷ and R⁸ taken together form a 4-12 membered mononitrogencontaining monocyclic or bicyclic ring optionally substituted with oneor more substituent selected from lower alkyl, carboxyl derivatives,aryl or hydroxy and wherein said ring optionally contains a heteroatomselected from the group consisting of O, N and S; R⁵ is selected fromthe group consisting of H and alkyl; or

wherein Y² is selected from the group consisting of alkyl; cycloalkyl;bicycloalkyl; aryl; monocyclic heterocycles; Z₁ is selected from thegroup consisting of CH₂, CH₂O, O, N, CO, S, SO, SO_(2,)

and NR_(k) wherein R_(k) is selected from H or lower alkyl; Z₂ is a 1-5carbon linker optionally containing one or more heteroatom selected fromthe group consisting of O, S and N; alternatively Z₁-Z₂ may furthercontain a carboxamide, sulfone, sulfonamide, alkenylene, alkynylene, oracyl group; wherein the carbon and nitrogen atoms of Z₁-Z₂ areoptionally substituted by alkyl, alkoxy, thioalkyl, alkylsulfone, aryl,alkoxyalkyl, hydroxy, alkylamino, heteroaryl, alkenyl, alkynyl,carboxyalkyl, halogen, haloalkyl or acylamino; wherein Z₂-Z₁ is attachedto

at the para or meta position relative to the X₁ substituent; n is aninteger 1 or 2; R^(c) is selected from the group consisting of hydrogen;alkyl; halogen, hydroxy, nitro, alkoxy, amino, haloalkyl, aryl,heteroaryl, alkoxyalkyl, aminoalkyl, hydroxyalkyl, thioalkyl,alkylamino, arylamino, alkylsulfonylamino, acyl, acylamino, sulfonyl,sulfonamide, allyl, alkenyl, methylenedioxy, ethylenedioxy, alkynyl,alkynylalkyl, carboxy, alkoxycarbonyl, carboxamido, cyano, and—(CH₂)_(n) COR wherein n is 0-2 and R is selected from hydroxy, alkoxy,alkyl and amino; X₁ is selected from the group consisting of —O—, CO,SO₂, NR^(m) and (CHR^(p))_(q); wherein R^(m) is H or alkyl; R^(p) is H,alkyl; alkoxy or hydroxy; q is 0 or 1; X₂ is selected from the groupconsisting of —CHR^(e)—, CO, SO_(2, O,) NR^(f) and S; wherein R^(f) is Hor alkyl; R^(e) is selected from the group consisting of H, alkyl,hydroxy and alkoxy; X or Y are independently selected from the groupconsisting of —CR^(g)— or —N— wherein R^(g) is selected from the groupconsisting of H, alkyl, haloalkyl, fluoro, alkoxyalkyl, alkynyl, aryl,heteroaryl, aralkyl, heteroaralkyl, alkylsulfone, hydroxyalkyl, hydroxy,alkoxy, and carboxyalkyl; optionally the group X—X₂—Y contains a moietyselected from the group consisting of acyl, alkyl, amino, ether,thioether, sulfone and olefin;

forms a 3-8 membered monocyclic ring system; or an 8-11 memberedbicyclic system; optionally saturated or unsaturated; the monocyclicring system optionally containing 1-2 heteroatoms selected from N, O andS; the bicyclic ring system optionally containing 1-4 heteroatomsselected from N, O and S, or optionally containing the group such as SO₂or CO; and optionally substituted with one or more substituent selectedfrom the group consisting of alkyl, halogen, cyano, carboalkoxy,haloalkyl, alkoxyalkyl, alkylsulfone, aryl, heteroaryl, arakyl,heteroarakyl, or alkoxy; R^(b) is X₃-R^(h) wherein X₃ is selected fromthe group consisting of O, S and NR^(j) wherein R^(h) and R^(j) areindependently selected from the group consisting of H, alkyl, acyl,aryl, aralkyl and alkoxyalkyl; and and n is 0 or
 1. 2. A compoundaccording to the claim 1,

wherein A¹, Z₁, Z₂, R^(b), R^(c), are as described in claim 1; X₁ is(CHR^(p))_(q); wherein q=0; B is a 3-, 4-, or a 5-membered ring obtainedby combining X—X₂—Y; A is a phenyl ring substituted with R^(c); n=1
 3. Acompound according to the claim 2,

wherein the ring B is a 3-member cyclopropyl ring; Y=CR^(g); whereinR^(g) is selected from the group consisting of H, alkyl, haloalkyl,alkoxyalkyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl,alkylsulfone, hydroxyalkyl, hydroxy, alkoxy, and carboxyalkyl; A is aphenyl ring substituted with R^(c); R^(b)=OH
 4. A compound according tothe claim 3 wherein R^(g) is selected from the followingsubstituents/groups

H, alkyl, CH₂B₁R (B₁=O, SO₂, S, CO; R=alkyl, aryl), CH₂OH,

R R=alkyl, aryl CH₂R₁ (R₁=aryl, heteroayl)
 5. A compound according tothe claim 3 wherein A¹ is selected from the following ring systems


6. A compound according to the claim 3 wherein ring A is a phenyl ring,and the side chains containing Z₁-Z₂ and X₁-X are connected para to eachother.
 7. A compound according to the claim 6 wherein the phenyl ring isoptionally substituted with one or more substituents selected from thegroup consisting of alkyl; halogen, hydroxy, alkoxy, haloalkyl, aryl,heteroaryl, alkoxyalkyl, sulfonamide, methylenedioxy, ethylenedioxy,alkynyl, and alkynylalkyl;
 8. A compound according to the claim 6wherein Z₁ is selected from the group consisting of CH₂, CH₂O, O,NR_(k), CO, S, SO, and SO₂. R_(k) is as defined in claim 1
 9. A compoundaccording to the claim 6 wherein A¹ is selected from the following ringsystems


10. A compound according to the claim 1,

wherein A¹, Z₁, Z₂, R^(b), R^(c), are as described in claim 1; X₁ is(CHR^(p))_(q); wherein q=o; A is a phenyl ring substituted with R^(c) Bis a 3-member ring obtained by combining X—X₂—Y; n=1 R_(m) and R_(n) areselected from the group consisting of H, alkyl, halogen, alkoxy,haloalkyl, alkoxyalkyl, alkylsulfone, cyano, carboalkoxy, aryl,heteroaryl, aralkyl and heteroaralkyl. R_(m) and R_(n) may from aspirocyclic ring system.
 11. A compound according to the claim 10wherein A¹ is selected from the following ring systems:


12. The intermediates of formula 2 for their utility in the synthesis ofα_(V)β₃ and/or α_(V)β₅ integrin antagonists.


13. A compound according to claim 1 selected from the group consistingof: 2-[4-[3-(2-pyridinylamino)propoxy]phenyl]cyclopropaneacetic acid2-[4-[3-(2-pyridinylamino)propoxy]phenyl]cyclopentaneacetic acid3-[4-[3-(2-pyridinylamino)propoxy]phenyl]cyclopentaneacetic acid2,2-difluoro-3-[4-[3(2-pyridinylamino)propoxy]phenyl]cyclopropaneaceticacid (2-{4-[2-(5,6, 7,8-Tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-phenyl}-cyclopropyl)-aceticacid 2-[3-methyl-4-[3-(2-pyridinylamino)propoxy]phenyl]cyclopropaneacetic acid(2-{4-[3-(1-H-Pyrazol-3-ylamino)-propoxy]-phenyl}-cyclopropyl)-aceticacid(2-{3-Fluoro-4-[3-(1-H-pyrazol-3-ylamino)-propoxy]-phenyl}-cyclopropyl)-aceticacid(1-Methyl-2-{4-[2-(6-methylamino-pyridin-2-yl)-ethoxy]-phenyl}-cyclopropyl)-aceticacid(2-{4-[2-(6-Ethylamino-pyridin-2-yl)-ethoxy]-phenyl}-1-methyl-cyclopropyl)-aceticacid[2-(4-{2-[6-(2-Methoxy-ethylamino)-pyridin-2-yl]-ethoxy}-phenyl)-1-methyl-cyclopropyl]-aceticacid[2-(4-{2-[6-(3-Methoxy-propylamino)-pyridin-2-yl]-ethoxy}-phenyl)-1-methyl-cyclopropyl]-aceticacid(2-{4-[2-(6-Acetylamino-pyridin-2-yl)-ethoxy]-phenyl}-1-methyl-cyclopropyl)-aceticacid[1-Methyl-2-(4-{2-[6-(2,2,2-trifluoro-ethylamino)-pyridin-2-yl]-ethoxy}-phenyl)-cyclopropyl]-aceticacid(2-{4-[2-(6-Ethylamino-pyridin-2-yl)-ethoxy]-phenyl}-cyclopropyl)-aceticacid[2-(4-{2-[6-(2-Methoxy-ethylamino)-pyridin-2-yl]-ethoxy}-phenyl)-cyclopropyl]-aceticacid[2-(4-{2-[6-(2,2,2-Trifluoro-ethylamino)-pyridin-2-yl]-ethoxy}-phenyl)-cyclopropyl]-aceticacid[2-(4-{2-[6-(3-Methoxy-propylamino)-pyridin-2-yl]-ethoxy}-phenyl)-cyclopropyl]-aceticacid(2-{4-[2-(6-Acetylamino-pyridin-2-yl)-ethoxy]-phenyl}-cyclopropyl)-aceticacid
 14. A pharmaceutical composition comprising a therapeuticallyeffective amount of a compound of claim 1 and a pharmaceuticallyacceptable carrier.
 15. A pharmaceutical composition comprising atherapeutically effective amount of a compound of claims 2-13 and apharmaceutically acceptable carrier.2-[2-methoxy-4-[3-(2-pyridinylamino)propoxy]phenyl]cyclopropaneaceticacid2-[2-methyl-4-[3-(2-pyridinylamino)propoxy]phenyl]cyclopropaneaceticacid2-[3-fluoro-4-[3-(2-pyridinylamino)propoxy]phenyl]cyclopropaneaceticacid2-[2-fluoro-4-[3-(2-pyridinylamino)propoxy]phenyl]cyclopropaneaceticacid2-[4-[2-[6-(methylamino)-2-pyridinyl]ethoxy]phenyl]cyclopropaneaceticacid2-[4-[2-(3,4-dihydro-2H-pyrido[3,2-b]-1,4-oxazin-6-yl)ethoxy]phenyl]-cyclopropaneaceticacid 3-[4-[3-(2-pyridinylamino)propoxy]phenyl]cyclobutaneacetic acid(2-{2-Methoxy-4-[3-(pyridin-2-ylamino)-propoxy]-phenyl}-cyclopropyl)-aceticacid(2-{2-Fluoro-4-[3-(pyridin-2-ylamino)-propoxy]-phenyl}-cyclopropyl)-aceticacid(2-{2-Acetoxy-4-[3-(pyridin-2-ylamino)-propoxy]-phenyl}-cyclopropyl)-aceticacid(1-Methyl-2-{4-[3-(pyridin-2-ylamino)-propoxy]-phenyl}-cyclopropyl)-aceticacid(1-Methoxymethyl-2-{4-[3-(pyridin-2-ylamino)-propoxy]-phenyl}-cyclopropyl)-aceticacid(1-Methanesulfonylmethyl-2-{4-[3-(pyridin-2-ylamino)-propoxy]-phenyl}-cyclopropyl)-aceticacid(1-Pyridin-3-yl-2-{4-[3-(pyridin-2-ylamino)-propoxy]-phenyl}-cyclopropyl)-aceticacid(1-Benzo[1,3]dioxole-5-yl-2-{4-[3-(pyridin-2-ylamino)-propoxy]-phenyl}-cyclopropyl)-aceticacid(1-(2,3-Dihydro-benzofuran-6-yl)-2-{4-[3-(pyridin-2-ylamino)-propoxy]-phenyl}-cyclopropyl)-aceticacid(1-Isoxazol-3-yl-2-{4-[3-(pyridin-2-ylamino)-propoxy]-phenyl}-cyclopropyl)-aceticacid(1-Isoxazol-5-yl-2-{4-[3-(pyridin-2-ylamino)-propoxy]-phenyl}-cyclopropyl)-aceticacid(1-Oxazol-5-yl-2-{4-[3-(pyridin-2-ylamino)-propoxy]-phenyl}-cyclopropyl)-aceticacid(2-{4-[3-(Pyridin-2-ylamino)-propoxy]-phenyl}-1-thiazol-5-yl-cyclopropyl)-aceticacid(1-Methyl-2-{4-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-phenyl}-cyclopropyl)-aceticacid(1-Methoxymethyl-2-{4-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-phenyl}-cyclopropyl)-aceticacid(1-Methanesulfonylmethyl-2-{4-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-phenyl}-cyclopropyl)-aceticacid(1-Pyridin-3-yl-2-{4-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-phenyl}-cyclopropyl)-aceticacid(1-(2,3-Dihydro-benzofuran-6-yl)-2-{4-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-phenyl}-cyclopropyl)-aceticacid(1-Benzo[1,3]dioxol-5-yl-2-{4-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-phenyl}-cyclopropyl)-aceticacid(1-Isoxazol-3-yl-2-{4-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-phenyl}-cyclopropyl)-aceticacid(1-Isoxazol-5-yl-2-{4-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-phenyl}-cyclopropyl)-aceticacid(1-Oxazol-5-yl-2-{4-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-phenyl}-cyclopropyl)-aceticacid(2-{4-[2-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-phenyl}-1-thiazol-5-yl-cyclopropyl)-aceticacid(2-{4-[3-(1-H-Imidazol-2-ylamino)-propoxy]-phenyl}-cyclopropyl)-aceticacid(2-{3-Fluoro-4-[3-(1-H-imidazol-2-ylamino)-propoxy]-phenyl}-cyclopropyl)-aceticacid(2-{3-Fluoro-4-[3-(3-H-imidazol-4-ylamino)-propoxy]-phenyl}-cyclopropyl)-aceticacid(2-{4-[3-(3-H-Imidazol-4-ylamino)-propoxy]-phenyl}-cyclopropyl)-aceticacid.
 16. A pharmaceutical composition comprising a therapeuticallyeffective amount of atleast one compound of claim 1 and apharmaceutically acceptable carrier/or additive and optionally otheractive ingredient
 17. A pharmaceutical composition comprising atherapeutically effective amount of atleast one compound of claims 2-15and a pharmaceutically acceptable carrier/or additive and optionallyother active ingredient
 18. A method for treating conditions mediated bythe α_(V)β₃ integrin in a mammal in need of such treatment comprisingadministering an effective α_(V)β₃ inhibiting amount of a compound ofclaim
 1. 19. A method for treating conditions mediated by the α_(V)β₃integrin in a mammal in need of such treatment compirisng administeringan effective α_(V)β₃ inhibiting amount of a compound of claims 2-13. 20.The method according to claim 16 wherein the condition treated is tumormetastasis.
 21. The method according to claim 17 wherein the conditiontreated is tumor metastasis.
 22. The method according to claim 16wherein the condition treated is solid tumor growth.
 23. The methodaccording to claim 17 wherein the condition treated is solid tumorgrowth.
 24. The method according to claim 16 wherein the conditiontreated is angiogenesis.
 25. The method according to claim 17 whereinthe condition treated is angiogenesis.
 26. The method according to claim16 wherein the condition treated is osteoporosis.
 27. The methodaccording to claim 17 wherein the condition treated is osteoporosis. 28.The method according to claim 16 wherein the condition treated ishumoral hypercalcemia of malignancy.
 29. The method according to claim17 wherein the condition treated is humoral hypercalcemia of malignancy.30. The method according to claim 16 wherein the condition treated issmooth muscle cell migration.
 31. The method according to claim 17wherein the condition treated is smooth muscle cell migration.
 32. Themethod according to claim 16 wherein restenosis is inhibited.
 33. Themethod according to claim 17 wherein restenosis is inhibited.
 34. Themethod according to claim 16 wherein atheroscelorosis is inhibited. 35.The method according to claim 17 wherein atheroscelorosis is inhibited.36. The method according to claim 16 wherein macular degeneration isinhibited.
 37. The method according to claim 17 wherein maculardegeneration is inhibited.
 38. The method according to claim 16 whereinretinopathy is inhibited.
 39. The method according to claim 17 whereinretinopathy is inhibited.
 40. The method according to claim 16 whereinarthritis is inhibited.
 41. The method according to claim 17 whereinarthritis is inhibited.
 42. A method for treating conditions mediated bythe α_(V)β₅ integrin in a mammal in need of such treatment comprisingadministering an effective α_(V)β₅ inhibiting amount of a compound ofclaim
 1. 43. A method for treating conditions mediated by the α_(V)β₅integrin in a mammal in need of such treatment compirisng administeringan effective α_(V)β₅ inhibiting amount of a compound of claim
 2. 44. Themethod according to claim 40 wherein the condition treated is tumormetastasis.
 45. The method according to claim 41 wherein the conditiontreated is tumor metastasis.
 46. The method according to claim 40wherein the condition treated is solid tumor growth.
 47. The methodaccording to claim 41 wherein the condition treated is solid tumorgrowth.
 48. The method according to claim 40 wherein the conditiontreated is angiogenesis.
 49. The method according to claim 41 whereinthe condition treated is angiogenesis.
 50. The method according to claim40 wherein the condition treated is osteoporosis.
 51. The methodaccording to claim 41 wherein the condition treated is osteoporosis. 52.The method according to claim 40 wherein the condition treated ishumoral hypercalcemia of malignancy.
 53. The method according to claim41 wherein the condition treated is humoral hypercalcemia of malignancy.54. The method according to claim 40 wherein the condition treated issmooth muscle cell migration.
 55. The method according to claim 41wherein the condition treated is smooth muscle cell migration.
 56. Themethod according to claim 40 wherein restenosis is inhibited.
 57. Themethod according to claim 41 wherein restenosis is inhibited.
 58. Themethod according to claim 40 wherein atheroscelorosis is inhibited. 59.The method according to claim 41 wherein atheroscelorosis is inhibited.60. The method according to claim 40 wherein macular degeneration isinhibited.
 61. The method according to claim 41 wherein maculardegeneration is inhibited.
 62. The method according to claim 40 whereinretinopathy is inhibited.
 63. The method according to claim 41 whereinretinopathy is inhibited.
 64. The method according to claim 40 whereinarthritis is inhibited.
 65. The method according to claim 41 whereinarthritis is inhibited.